Prostaglandin synthase inhibitors

ABSTRACT

This invention relates to ortho substituted phenyl compounds as inhibitors of prostaglandin synthase, to pharmaceutical compositions comprising such compounds and to methods of using such compounds as antiinflammatory and antipyretic agents. The class of compounds useful in this method of treatment is represented by Formula I below: ##STR1##

FIELD OF THE INVENTION

This invention relates to ortho substituted phenyl compounds asinhibitors of prostaglandin synthase, to pharmaceutical compositionscomprising such compounds and to methods of using such compounds asantiinflammatory and antipyretic agents.

BACKGROUND

Nonsteroidal antiinflammatory drugs (NSAID's) have been the mainstay ofantirheumatic and antiinflammatory drug therapy for over 200 years(Weissman, G., Scientific American 84-90, 1991). NSAID's functionthrough inhibition of prostaglandin biosynthesis (Vane, J. R.,Nature-New Biology 231, 232-235, 1971). Specifically, these agents actas cyclooxygenase (prostaglandin G/H synthase) inhibitors.Cyclooxygenase is the first enzyme in the arachidonic acid cascade,leading to prostaglandins of the D₂, E₂, and F₂ a series. In addition,prostacyclin (PGI2) and thromboxanes A₂ and B₂ are derived from acyclooxygenase-generated PGHS₂ intermediate (Prostaglandins and RelatedSubstances--A Practical Approach (1987) . Benedetto, C.,McDonald-Gibson, R. G., and Nigam, S., and Slater, T. F., eds IRL Press,Washington, D.C). These arachidonic acid metabolites are involved in theprocesses of pain, fever, blood clotting and inflammation. In addition,prostaglandins are responsible for maintaining gastrointestinal mucosalintegrity (Cryer, B., and Feldman, M., Arch Intern. Med. 152, 1145-1155,1992) and renal function, particularly under conditions of stress(Whelton, A., and Hamilton, C. W., J. Clin. Pharmacol. 31, 588-598,1994). Thus, agents which inhibit the cyclooxygenase enzyme havebeneficial antiinflammatory and analgesic properties Cue to blockade ofinflammatory and pain-mediator production, but by virtue of theirmechanism of action, these same agents have liabilities associated withgastrointestinal and renal function. Minimizing or eliminating theseliabilities in a new therapy provides the rationale for searching for a"safe" NSAID with an improved GI and renal profile (Vane, J. R., Nature367, 215-216, 1994).

Until recently, it had been assumed that only one cyclooxygenase isozymewas responsible for all prostaglandin G/H2 synthase activity. However, anewly identified, mitogen-inducible form of this enzyme, termedcyclooxygenase 2 (Cox 2), has been described (Xie, W., Chipman, J. G.,Robertson, D. L., Erickson, R. L., and Simmons, D. L., Proc. Natl. Acad.Sci. 88, 2692-2696, 1991; Kujubu, D. A., Fletcher, B. S., Varnum, B. C.,Lira, R. W., and Herschman, H. R., J. Biol. Chem. 266(20) 12866-12872,1991; Hla, T., and Neilson, K., Proc. Natl. Acad. Sci. 89, 7384-7388,1991; Xie, W., Robertson, D. L., and Simmons, D .L., Drug DevelopmentResearch 25, 249-265, 1992). Cox 2 displays physical and biologicalproperties distinct from the classic cyclooxygenase species, Cox 1. Thetissue and cellular distribution of Cox 2, along with its regulatedexpression, implicate its involvement in inflammatory responses anddisease states such as rheumatoid arthritis, while Cox 1 expression isresponsible for constitutive functions. Based upon the distinctionbetween Cox 1 and Cox 2, the previous hypotheses explaining NSAIDeffects, which rely on a single isozyme, must be questioned.Specifically, the antiinflammatory and analgesic action of NSAID'sattributed exclusively to inhibition of the constitutive Cox 1 isozymecannot be accepted. In fact, a more probable hypothesis is that theantiinflammatory and analgesic action of most NSAID's in response to achronic stimulus can be accounted for by inhibition of the inducible Cox2 species, while GI and renal liabilities of existing NSAID's are due toinhibition of the constitutively expressed Cox 1 enzyme (Vane, J. R.,Nature 367, 215-216, 1994). Thus, agents which possess selective orspecific inhibition of Cox 2 can be expected to provide improved GI andrenal safety while maintaining a high degree of antiinflammatory,antipyretic and analgesic activity.

The potential for a safer NSAID through selective inhibition hasprompted evaluation of compounds on purified enzyme preparations.Preferential inhibition of either isoenzyme or equal inhibitory potencyhas been obtained with a collection of therapeutically useful NSAIDS(DeWitt, D. L., Meade, E. A., and Smith, W. L., Amer. J. Med. 95 (Suppl.2A), 40S--44S, 1993). Only one compound in this collection, however,displayed Cox 2 selectivity, namely 6-methoxy naphthylacetic acid(6MNA), the nebumetone active metabolite. Several other agents withsimilar Cox-2 selectivity have also been described including BF389(Mitchell, J. A., Akarasereenot, P., Thiemermann, C., Flower, R. J., andVane, J. R., Proc. Natl. Acad. Sci. 90, 11693-11697, 1994) and NS-398(Futaki, N., Takahashi, S., Yokayama, M. , Arai, I., Higuchi, S., andOtomo, S., Prostaglandins 47, 55-59, 1994; Masferrer, J. L., Zuieifel,B. S., Manning, P. T., Hauser, S. D., Leaky, K. M., Smith, W. G. ,Isakson, P. C. , and Seibert, K., Proc. Natl. Acad. Sci. 91, 3228-3232,1994). With the latter compound, selective inhibition of Cox-2 blockedproinflammatory prostaglandin synthesis in vivo in response tocarrageenan, but did not block gastric prostaglandin synthesis norproduce gastic lesions (Masferrer et al, vide supra).

The findings support the premise that selective Cox-2 inhibitors willpossess potent antiiflammatory properties and improved safety profile.Detailed mechanistic studies have revealed that NS-398 along with asecond Cox-2 selective inhibitor, DuP 697, achieve their selectivitythrough a unique process (Copeland, R. A., Williams, J. M., Giannaras,J., Nurnberg, S., Covington, M., Pinto, D., Pick, S., and Trzaskos, J.M. Mechanism of Selective Inhibition of the Inducible Isoform ofProstaglandin G/H Synthase. Submitted). The inhibition is competitivetoward both isoenzymes, but displays selective time-dependence againstCox-2 resulting in enhanced inhibition with longer exposure.Time-dependence produces an extremely tight binding inhibition which canonly be reversed following enzyme denaturation and organic extraction.

Newkome G. R. et. al. (J. Org. Chem. 1980, 45, 4380) reportbis-(5-carboxy-2-pyridyl)benzenes, but no utility for these compounds isdisclosed. ##STR2##

Bushby et. al. (J. Chem. Soc. Perkin Trans. I 721, 1986) describe thesynthesis of substituted terphenyls including the example shown below.##STR3##

Hori M. et. al. (Chem. Pharm. Bull. 22(9), 2020, 1974) report thesynthesis of terphenyls, including 2-phenyl-2'-methylthio-1-biphenyl.##STR4##

Kemp et. al. (J. Org. Chem. 46, 5441, 1981), report the synthesis of4-methoxyphenyl-(4'-alkylphenyl)benzenes. ##STR5##

Floyd et. al., U.S. Pat. No. 4,613,611 disclose α-hydroxy-β-oxo-[1,1':2',1"-terphenyl]-4-ethanesulfonic acid, monosodium salt for thetreatment of Diabetes Mellitus. ##STR6##

Ortho-bis (dimethoxyphenyl) benzene carboxamides have been reported(Tilley, et. al. J. Med. Chem. 32, 1814, 1989) as platelet-activatingfactor antagonists. ##STR7##

European Patent Application EP130045 Al, published Jan. 2, 1985discloses substituted bis-(methoxyphenyl)benzenes as analgesic andantiinflammatory agents. ##STR8##

U.S. Pat. No. 3,624,142 discloses 4-methylsulfonyl-biphenylacetic acidsas antiflammatory agents. ##STR9##

None of the above references teach or suggest the methylsulfonylcompounds of the present invention. Thus, it is the object of thepresent invention to provide compounds which are prostaglandin synthaseinhibitors, including compounds which are selective Cox 2 inhibitors, asnovel antiinflammatory agents with an improved therapeutic profile foruse in rheumatic and inflammatory diseases and in the treatment ofpyresis.

SUMMARY OF THE INVENTION

This invention relates to ortho substituted phenyls of Formula Idescribed below as inhibitors of prostaglandin synthase, topharmaceutical compositions comprising such compounds and to methods ofusing such compounds as antiinflammatory and antipyretic agents.

DETAILED DESCRIPTION OF THE INVENTION

There is provided by this invention a compound of Formula I: ##STR10##or a pharmaceutically acceptable salt or prodrug form thereof, wherein:J, K, and L are independently CR³, CR⁴ or N;

X is a single bond, (i.e. X is absent), --(CHR⁵)₂ --, --CH═CR⁵ --, --CR⁵═CH--, --C═, --(CHR⁵)_(p) Z--, --Z(CHR⁵)_(p) --, --C(═O)CH₂, or --CH₂C(═O)--;

Z is O or S;

R¹ is:

phenyl substituted with 0-2 R⁷,

2-naphthyl substituted with 0-2 R⁷,

C₅ -C₇ cycloalkyl substituted with 0-1 R⁹,

C₅ -C₇ cycloalkenyl, provided that when R¹ is attached directly to aheteroatom, said heteroatom is not attached to a carbon bearing a doublebond in the cycloalkene ring,

a 5- to 10-membered heterocyclic ring system selected from furyl,thienyl, pyrrolyl, thiazolyl, oxazolyl, N-methylpyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, 3-pyridinyl, pyrazinyl, benzofuranyl,benzothienyl, benzothiazolyl, benzoxazolyl, benzotriazolyl,benzoisothiazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, orpiperidinyl, said heterocyclic ring system being substituted with 0-2 R⁷;

R² is: ##STR11## Y is --CH₃ or NH₂ ; R³ is: H, F, Br, Cl, I, CN, C₁ -C₄alkyl substituted with 0-1 R¹² C₁ -C₄ haloalkyl, C₁ -C₄ alkenylsubstituted with 0-1 R¹³, NO₂, NR¹⁵ R¹⁶, S(O)_(m) R¹¹, SO₂ NR^(15a) R¹⁶,--C(═O)R⁶, --COOR¹⁷, --C(═O)NR^(15a) R¹⁶, or OR¹⁸ ;

R⁴ is H, F, Br, Cl, I, C₁ -C₂ alkyl, C₁ -C₂ alkoxy, C₁ -C₂ haloalkyl,--CF₃, --SR^(10a) ;

alternately, when R³ and R⁴ are substituents on adjacent carbon atoms,R³ and R⁴ can be taken together with the carbon atoms to which they areattached to form a 5-7 membered carbocyclic or heterocyclic ring system,said heterocyclic ring system containing from 1-3 heteroatoms selectedfrom N, O or S;

R⁵ is C₁ -C₂ alkyl, C₁ -C₂ alkoxy, or C₁ -C₂ haloalkyl;

R⁶ is

hydrogen,

C₁ -C₆ alkyl substituted with 0-1 R¹⁴, phenyl substituted with 0-2 R⁹,

C₅ -C₇ cycloalkyl substituted with 0-1 R⁹,

a 5- to 10-membered heterocyclic ring system selected from furyl,thienyl, thiazolyl, oxazolyl, N-methylpyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrazinyl, orpyrimidinyl, said heterocyclic ring system being substituted with 0-2 R⁷;

R⁷ is a substituent on carbon that is selected from: H, F, Br, Cl, I, C₁-C₄ alkyl, phenyl, CH₂ OH, CH₂ OCH₃, C₁ -C₄ alkoxy, C₁ -C₄ haloalkyl,--SR¹⁰, NR¹⁵ R¹⁶, --C(═O)R^(10a), CH₂ COOR¹⁷, or OR¹⁹ ; provided thatwhen X is a single bond then R⁷ is not ortho to X.

R⁸ is H, F, Br, Cl, I, C₁ -C₄ alkyl, C₁ -C₄ alkoxy;

R⁹ is H, F, Br, Cl, I, hydroxy, C₁ -C₄ alkyl, or C₁ -C₄ alkoxy;

R¹⁰ is H or C₁ -C₄ alkyl;

R^(10a) C₁ -C₄

R¹¹ is C₁ -C₄ alkyl, C₁ -C₂ fluoroalkyl, phenyl, or benzyl;

R¹² is F, OR¹⁸, NR¹⁵ R¹⁶, phenyl substituted with 0-2 R⁹, --CN,--C(═O)R⁶, --COOR¹⁷, --C(═O)NR¹⁵ R¹⁶, or

a heterocyclic ring system selected from morpholinyl, piperidinyl,pyrrolidinyl, furyl, thienyl, pyridinyl, piperidazinyl, pyrimidinyl,pyrazinyl, or tetrahydropyridinyl, said heterocyclic ring system beingsubstituted with 0-2 R⁹ ;

R¹³ is --CN, --C(═O)R⁶, --COOR¹⁷, --NO₂, or NR¹⁵ R¹⁶ ;

R¹⁴ is F, OH, C₁ -C₄ alkoxy, NH₂, phenyl substituted with 0-2 R⁹,alkylcarbonyl, arylcarbonyl, --COOR¹⁷, or --C(═O)NH₂ ;

R¹⁵ is H, C₁ -C₄ alkyl substituted with 0-1 R²³, C₆ -C₁₀ aryl, C₃ -C₇cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₂ -C₄ alkenyl, C₁ -C₄ alkoxy, C₁-C₆ alkylcarbonyl, C₁ -C₆ alkoxycarbonyl, C₇ -C₁₄ arylalkoxycarbonyl, C₆-C₁₀ aryloxycarbonyl, C₁ -C₆ alkylaminocarbonyl, C₆ -C₁₀ arylcarbonyl,C₁ -C₆ alkylsulfonyl, C₆ -C₁₀ arylsulfonyl, C₇ -C₁₄ alkylarylsulfonyl,or C₇ -C₁₄ arylalkylsulfonyl;

R^(15a) is H, C₁ -C₄ alkyl substituted with 0-1 R²³, C₆ -C₁₀ aryl, C₃-C₇ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₂ -C₄ alkenyl, or C₁ -C₄alkoxy;

R¹⁶ is H, or C₁ -C₄ alkyl; or

Alternately, R¹⁵ and R¹⁶ can be taken together to be --(CH₂)₄ --,--(CH₂)₅ --, --(CH₂)₂ O(CH₂)₂ --, or --(CH₂)₂ NR²¹ (CH₂)₂ --,

R¹⁷ is C₁ -C₄ alkyl, or arylalkyl;

R¹⁸ is C₁ -C₄ alkyl substituted with 0-2 R²⁴, C₆ -C₁₀ aryl, C₃ -C₇cycloalkyl, C₁ -C₆ alkylcarbonyl, C₁ -C₆ alkylaminocarbonyl, C₇ -C₁₄arylalkylcarbonyl, or C₆ -C₁₀ arylcarbonyl substituted with 0-2 R⁹ ;

R¹⁹ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₁ -C₄ alkoxyalkyl, C₁ -C₆alkylcarbonyl, C₁ -C₆ alkylaminocarbonyl, C₇ -C₁₄ arylalkylcarbonyl, orC₆ -C₁₀ arylcarbonyl substituted with 0-2 R⁹ ;

R²⁰ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₁ -C₄ alkoxyalkyl, C₆ -C₁₀ aryl,C₃ -C₇ cycloalkyl, C₁ -C₆ alkylcarbonyl, C₁ -C₆ alkylaminocarbonyl, C₇-C₁₄ arylalkylcarbonyl, or C₆ -C₁₀ arylcarbonyl substituted with 0-2 R⁹;

R²¹ is C₁ -C₄ alkyl or benzyl;

R²² is H, R², R¹, C₁ -C₄ alkyl, C₄ -C₁₀ cycloalkylalkyl, C₇ -C₁₄arylalkyl, or C₆ -C₁₀ heteroarylalkyl;

R²³ is H, F, phenyl substituted with 0-2 R⁹, --C(═O)R⁶, --COOR¹⁷,--C(═O)NHR¹⁶, or

a heterocyclic ring system selected from morpholinyl, piperidinyl,pyrrolidinyl, furyl, thienyl, or tetrahydropyridinyl, said heterocyclicring system being substituted with 0-2 R⁹ ;

R²⁴ is:

H, F, NR¹⁵ R¹⁶, phenyl substituted with 0-2 R⁹, C₁ -C₄ alkoxy, C₁ -C₄alkylcarbonyloxy, C(═O)R⁶, --COOR¹⁷, --C(═O)NR¹⁵ R¹⁶, or a heterocyclicring system selected from morpholinyl, piperidinyl, pyrrolidinyl, furyl,thienyl, or tetrahydropyridinyl, said heterocyclic ring system beingsubstituted with 0-2 R⁹ ;

m is 0-2; and

p is 0-1.

provided that when J and L are both nitrogen and K is CR⁴, then R⁴cannot be SR¹⁰.

Preferred are compounds of Formula I or pharmaceutically acceptablesalts or prodrugs thereof, wherein:

J is CH or N;

each of K and L independently is CR³ or CR⁴ ;

X is a single bond, (i.e. X is absent), --C.tbd.C--, or --(CHR⁵)_(p)Z--;

R³ is: H, F, Br, CN, C₁ -C₄ alkyl substituted with 0-1 R¹² C₁ -C₄haloalkyl, NO₂, SO_(m) R¹¹, --C(═O)R⁶, or OR¹⁸ ;

R⁴ is H, F, CH₃, or

alternately, when R³ and R⁴ are substituents on adjacent carbon atoms,R³ and R⁴ can be taken together with the carbon atoms to which they areattached to form a 5-7 membered carbocyclic ring system;

R⁶ is

hydrogen,

C₁ -C₆ alkyl substituted with 0-1 R¹⁴, or

phenyl substituted with 0-2 R⁹ ; and

R⁷ is a substituent on carbon that is selected from: H, F, Br, C₁ -C₄alkyl, CH₂ OH, CH₂ OCH₃, C₁ -C₄ alkoxy, C₁ -C₄ haloalkyl, NR¹⁵ R¹⁶, or--C(═O)R¹⁰ ; and

where all other substituents for Formula I are as defined herein above.

Further preferred are the preferred compounds of Formula I, orpharmaceutically acceptable salts or prodrugs thereof, wherein:

R⁸ is H;

R⁹ is H;

R¹² is F, OR¹⁸, CN--COOR¹⁷ ;

R¹⁴ is H;

R¹⁵ is H, or C₁ -C₄ alkyl;

R¹⁶ is H or C₁ -C₄ alkyl;

R¹⁸ is H or C₁ -C₄ alkyl;

R¹⁹ is C₁ -C₄ alkyl.

Specifically preferred are compounds, or pharmaceutically acceptablesalts or prodrugs, thereof, selected from the group consisting of:

(a) compounds of Formula Ia: ##STR12## wherein: R¹ X is phenyl and R³ ishydrogen,

R¹ X is phenyl and R³ is 4-OH,

R¹ X is phenyl and R³ is 4-NO₂,

R¹ X is phenyl and R³ is 5-NO₂,

R¹ X is phenyl and R³ is 4-CH₃ C(═O),

R¹ X is 4-fluorophenyl and R³ is H,

R¹ X is 4-methoxyphenyl and R³ is H,

R¹ X is 4-methylphenyl and R³ is H,

R¹ X is 3-methoxyphenyl and R³ is H,

R¹ X is 3,4-dimethoxyphenyl and R³ is H,

R¹ X is 4-hydroxymethylphenyl and R³ is H,

R¹ X is 4-methoxymethylphenyl and R³ is H,

R¹ X is 4-dimethylaminophenyl and R³ is H,

R¹ X is 4-formylphenyl and R³ is H,

R¹ X is 2-naphthyl and R³ is H,

R¹ X is 5-methoxy-2-naphthyl and R³ is H,

R¹ X is 3-quinolinyl and R³ is H,

R¹ X is 2-quinolinyl and R³ is H,

R¹ X is 5-benzothienyl and R³ is H,

R¹ X is 2-benzothienyl and R³ is H,

R¹ X is 3-pyridyl and R³ is H,

R¹ X is PhC.tbd.C- and R³ is H,

R¹ X is phenoxy and R³ is H,

R¹ X is 1-cyclohexenyl and R³ is H,

R¹ X is cyclohexyl and R³ is H,

R¹ X is 4-fluorophenoxy and R³ is H,

R¹ X is cyclohexyloxy and R³ is H,

R¹ X is benzyloxy and R³ is H,

R¹ X is 1-piperidinyl and R³ is H,

R¹ X is 1-pyrrolyl and R³ is H,

(b) the compound of Formula I which is2-(4-methylsulfonylphenyl)-3-phenylnaphthalene,

(c) the compound of Formula I which is3-(4-methylsulfonylphenyl)-2-phenylpyridine, and

(d) the compound of Formula I which is2-(4-aminosulfonylphenyl)-1-biphenyl.

The present invention also provides pharmaceutical compositionscomprising a compound of Formula I and a pharmaceutically acceptablecarrier.

The compounds described above are useful as antiinflammatory andantipyretic agents in a mammal when administered as pharmaceuticalcompositions to a mammal in need of treatment with such antiinflammatoryor antipyretic agents. The present invention includes pharmaceuticalcompositions containing an effective PGHS-2-inhibiting orantiinflammatory or antipyretic amount of the above described compoundsof Formula I. The present invention also includes methods of treatingarthritis and other inflammatory diseases in a mammal comprisingadministering to the mammal a therapeutically effective amount of acompound of Formula I described above.

The compounds of the present invention can also be administered incombination with one or more additional therapeutic agents.Administration of the compounds of Formula I of the invention incombination with such additional therapeutic agent, may afford anefficacy advantage over the compounds and agents alone, and may do sowhile permitting the use of lower doses of each. A lower dosageminimizes the potential of side effects, thereby providing an increasedmargin of safety.

By "therapeutically effective amount" it is meant an amount of acompound of Formula I that when administerea alone or in combinationwith an additional therapeutic agent to a cell or mammal is effective toinhibit PGHS-2 so as to prevent or ameliorate the inflammatory diseasecondition or the progression of the disease

By "administered in combination" or "combination therapy" it is meantthat the compound of Formula I and one or more additional therapeuticagents are administered concurrently to the mammal being treated. Whenadministered in combination each component may be administered at thesame time or sequentially in any order at different points in time.Thus, each component may be administered separately but sufficientlyclosely in time so as to provide the desired therapeutic effect.

The compounds herein described may have asymmetric centers. Unlessotherwise indicated, all chiral, diastereomeric and racemic forms areincluded in the present invention. Many geometric isomers of olefins,C=N double bonds, and the like can also be present in the compoundsdescribed herein, and all such stable isomers are contemplated in thepresent invention. It will be appreciated that compounds of the presentinvention may contain asymmetrically substituted carbon atoms, and maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis, from optically active starting materials.All chiral, diastereomeric, racemic forms and all geometric isomericforms of a structure are intended, unless the specific stereochemistryor isomer form is specifically indicated.

When any variable occurs more than one time in any constituent or in anyFormula, its definition on each occurrence is independent of itsdefinition at every other occurrence. Thus, for example, if a group isshown to be substituted with 0-3 R⁶, then said group may optionally besubstituted with up to three R⁶ and R⁶ at each occurrence is selectedindependently from the defined list of possible R⁶. Also, by way ofexample, for the group --N(R^(5a))₂, each of the two R^(5a) substituentson N is independently selected from the defined list of possible R^(5a).Similarly, by way of example, for the group --C(R⁷)₂ --, each of the twoR⁷ substituents on C is independently selected from the defined list ofpossible R⁷.

When a bond to a substituent is shown to cross the bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering.

When a substituent is listed without indicating the atom via which suchsubstituent is bonded to the rest of the compound of Formula I, thensuch substituent may be bonded via any atom in such substituent. Forexample, when the substituent is piperazinyl, piperidinyl, ortetrazolyl, unless specified otherwise, said piperazinyl, piperidinyl,tetrazolyl group may be bonded to the rest of the compound of Formula Ivia any atom in such piperazinyl, piperidinyl, tetrazolyl group.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. By stable compound orstable structure it is meant herein a compound that is sufficientlyrobust to survive isolation to a useful degree of purity from a reactionmixture, and Formulation into an efficacious therapeutic agent.

The term "substituted", as used herein, means that any one or morehydrogen on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

As used herein, "alkyl" is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms (for example, "C₁ -C₁₀ " denotes alkylhaving 1 to 10 carbon atoms); "haloalkyl" is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morehalogen (for example --C_(v) F_(w) where v=1 to 3 and w=1 to (2v+1));"alkoxy" represents an alkyl group of indicated number of carbon atomsattached through an oxygen bridge; "alkylthio" represents an alkyl groupof indicated number of carbon atoms attached through a sulfur bridge;"dialkylamino" represents a N atom substituted with 2 alkyl groups ofthe indicated number of carbon atoms; "cycloalkyl" is intended toinclude saturated ring groups, including mono-,bi- or polycyclic ringsystems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, and adamantyl; and "bicycloalkyl" is intendedto include saturated bicyclic ring groups such as [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),[2.2.2]bicyclooctane, and so forth. "Alkenyl" is intended to includehydrocarbon chains of either a straight or branched configuration andone or more unsaturated carbon-carbon bonds which may occur in anystable point along the chain, such as ethenyl, propenyl and the like;and "alkynyl" is intended to include hydrocarbon chains of either astraight or branched configuration and one or more triple carbon-carbonbonds which may occur in any stable point along the chain, such asethynyl, propynyl and the like.

The terms "alkylene", "alkenylene", "phenylene", and the like, refer toalkyl, alkenyl, and phenyl groups, respectively, which are connected bytwo bonds to the rest of the structure of Formula I. Such "alkylene","alkenylene", "phenylene", and the like, may alternatively andequivalently be denoted herein as "-(alkyl)-", "-(alkenyl)-" and"-(phenyl)-", and the like.

"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo andiodo; and "counterion" is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate and thelike.

As used herein, "aryl" or "aromatic residue" is intended to mean phenylor naphthyl; the term "arylalkyl" represents an aryl group attachedthrough an alkyl bridge.

As used herein, "carbocycle" or "carbocyclic residue" is intended tomean any stable 3- to 7-membered monocyclic or bicyclic or 7- to14-membered bicyclic or tricyclic or an up to 26-membered polycycliccarbon ring, any of which may be saturated, partially unsaturated, oraromatic. Examples of such carbocyles include, but are not limited to,cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl,indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term "heterocycle" or "heteroaryl" or "heterocyclic"is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or7-to 10-membered bicyclic heterocyclic ring which may be saturated,partially unsaturated, or aromatic, and which consists of carbon atomsand from 1 to 4 heteroatoms independently selected from the groupconsisting of N, O and S and wherein the nitrogen and sulfur heteroatomsmay optionally be oxidized, and the nitrogen may optionally bequaternized, and including any bicyclic group in which any of theabove-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom which results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. Examples of such heterocyclesinclude, but are not limited to, pyridyl (pyridinyl), pyrimidinyl,furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, pyrrolidinyl, 2-pyrrolinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, octahydroisoquinolinyl, pyranyl, isobenzofuranyl,2H-pyrrolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl,indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, pyrrolidinyl,pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperidinyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl oroxazolidinyl. Also included are fused ring and spiro compoundscontaining, for example, the above heterocycles.

As used herein, "pharmaceutically acceptable salts" refer to derivativesof the disclosed compounds wherein the parent compound of Formula I ismodified by making acid or base salts of the compound of Formula I.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like.

"Prodrugs" are considered to be any covalently bonded carriers whichrelease the active parent drug according to Formula I in vivo when suchprodrug is administered to a mammalian subject. Prodrugs of thecompounds of Formula I are prepared by modifying functional groupspresent in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds of Formula I wherein hydroxyl,amino, sulfhydryl, or carboxyl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofFormula I, and the like.

The pharmaceutically acceptable salts of the compounds of Formula Iinclude the conventional non-toxic salts or the quaternary ammoniumsalts of the compounds of Formula I formed, for example, from non-toxicinorganic or organic acids. For example, such conventional non-toxicsalts include those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; andthe salts prepared from organic acids such as acetic, propionic,succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the compounds of Formula I which contain a basic oracidic moiety by conventional chemical methods. Generally, the salts areprepared by reacting the free base or acid with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidor base in a suitable solvent or various combinations of solvents.

The pharmaceutically acceptable salts of the acids of Formula I with anappropriate amount of a base, such as an alkali or alkaline earth metalhydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or anorganic base such as an amine, e.g., dibenzylethylenediamine,trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or aquaternary ammonium hydroxide such as tetramethylammoinum hydroxide andthe like.

As discussed above, pharmaceutically acceptable salts of the compoundsof the invention can be prepared by reacting the free acid or base formsof these compounds with a stoichiometric amount of the appropriate baseor acid, respectively, in water or in an organic solvent, or in amixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa. 1985, p. 1418, the disclosureof which is hereby incorporated by reference.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of Formula I may be prepared using the reactions andtechniques described in this section. The reactions are performed insolvents appropriate to the reagents and materials employed and aresuitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe educt molecule must be compatible with the reagents and reactionsproposed. Not all compounds of Formula I falling into a given class maybe compatible with some of the reaction conditions required in some ofthe methods described. Such restrictions to the substituents which arecompatible with the reaction conditions will be readily apparent to oneskilled in the art and alternate methods must then be used.

Compounds of Formula I wherein R¹ is a substituted aryl, X is a singlebond (i.e. X is absent), R² is a 4-methylsulfonylphenyl and R³, R⁴, R⁷and R⁸ are defined as above, can be prepared following the generalmethod illustrated in Scheme 1. ##STR13##

Coupling of a suitably substituted phenylboronic acid with anortho-dibromobenzene using methodology introduced by Suzuki (A. Suzukiet al., J. Am. Chem. Soc., 1989, 11, 513 and V. N. Kalinin, Russ. Chem.Rev., 1991, 60, 173) affords a mixture of 2-bromobiphenyl A and1,2-diarylbenzene. Suitable solvents for this coupling include but arenot limited to toluene, dimethylformamide, dioxane and ethanol. Thereaction is carried out in the presence of a palladium catalyst, forexample, tetrakis triphenylphosphine palladium orbis(triphenylphosphine)palladium dichloride. Removal of the biscouplingproduct can be achieved using standard chromatographic techniques knownto those skilled in the art of organic synthesis to give the desiredbiphenyl intermediate. A second Suzuki coupling of this 2-bromobiphenylwith a 4-methylthio-phenylboronic acid using the conditions describedabove provides 2-(4'-methylthio)phenyl-1-biphenyl. Oxidation of themethylthio group to the corresponding methylsulfonyl group gives acompound of Formula I. This oxidation can be accomplished using any ofthe reagents known in the art for the oxidation of mercaptans tosulfones. Examples of such reagents include, but are not limited to,oxone in methanol-water (Trost et. al. Tet. Lett. 22 (14), 1287, 1981),hydrogen peroxide, m-chloroperbenzoic acid, or monoperoxyphthalic acid,magnesium salt.

Alternatively, compounds of Formula I, wherein R¹ is a substituted aryl,X is a single bond, and R² is a 4-methylsulfonylphenyl can also beprepared from commercially available 2-bromophenols as depicted inScheme 2. Suzuki coupling of a 2-bromophenol with a phenylboronic acidcan be carried out under the conditions described above using either thefree or suitably protected phenol, or the corresponding triflate. Asecond Suzuki coupling between the intermediate triflate and a4-methylthiophenylboronic acid followed by oxidation as previouslydescribed gives compounds of Formula I. ##STR14##

Compounds of Formula I wherein R² is a 4-methylsulfonylphenyl, X is asingle bond and R¹ is a cycloalkenyl or cycloalkyl moiety, are preparedfrom 2-bromo-(4'-methylthio)biphenyls by the series of steps outlined inScheme 3. The required biphenyl starting materials are obtained bySuzuki coupling of 1,2-dibromobenzene with 4-methylthiophenylboronicacid using conditions described above.

Treatment of 2-bromo-(4'-methylthio)biphenyl with a strong base at lowtemperature followed by the addition of a suitable cycloalkanoneprovides a (1-hydroxycycloalkyl)biphenyl intermediate. Suitable strongbases that can be used in this reaction include n-butyllithium,t-butyllithium, or methyllithium. The reaction is run in an aproticsolvent such as tetrahydrofuran, ether, hexane or 1,4-dioxane.Dehydration of the resulting tertiary alcohol can be readilyaccomplished by treatment with a catalytic amount of a strong acid, e.g.p-toluenesulfonic acid, in a suitable solvent, e.g. toluene. Oxidationof the methylthio group to the methyl sulfonyl as described above givescompounds of Formula I wherein R¹ is cycloalkenyl. Catalytichydrogenation of these cycloalkenyl compounds over a suitable catalyst,for example, platinum oxide, in a suitable polar solvent, for example,methanol, provides compounds of Formula I wherein R¹ is cycloalkyl.Alternatively the cycloalkyl compounds may be obtained from the alcoholintermediate by first oxidizing the methylthio group to themethylsulfone followed by direct hydrogenation of the tertiary alcoholsusing the same hydrogenation conditions described above for thereduction of the olefin. ##STR15##

Compounds of Formula I wherein X ms oxygen, R¹ is substituted orunsubstituted phenyl and R² is 4-methylsulfonylphenyl can be preparedfrom 2-hydroxy-(4'-methylthio)biphenyl as outlined in Scheme 4.##STR16##

Treatment of 2-hydroxy-l-(4'-methylsulfonyl)biphenyl (prepared viasynthetic Scheme 2) with a suitable base, for example, sodium hydride,followed by the addition of 4-fluoro-l-nitrobenzene provides a2-(4-nitrophenoxy)biphenyl intermediate. Reduction of the nitro group(see "Compendium of Organic Synthetic Methods" vol. 1 p. 266, 1971)gives a compound of Formula I where R⁷ =NH₂. Deamination can be achievedusing the method of Cadogan, J. I. G. et. al. (J. Chem. Soc. Perkin.Trans. I 541, 1973). Alternately, the amine can be transformed intoother functionalities via an intermediate diazonium salt using methodswell known to one skilled in the art of organic synthesis. By employingthis methodology other appropriately substituted aryl ethers of FormulaI can easily be prepared.

Compounds of Formula 2 wherein R² is 4-methylsulfonylheteroaryl may beprepared by palladium-catalyzed Suzuki coupling of 2-biphenylboronicacid with an appropriately substituted 4-methylthioheteroaryl bromide ortriflate (see Scheme 5). Oxone oxidation selectively provides thedesired methylsulfonyl compounds. ##STR17##

The 2-methylthio-5-bromo-pyridine reagents in Scheme 5 may be preparedin one step from commercially available 2,5-dibromopyridines asillustrated in Scheme 6 by treatment with an alkaline salt of methylmercaptan, for example sodium methylthiolate, in a polar, aproticsolvent such as anhydrous dimethylformamide. ##STR18##

Other bromo or hydroxy methylthio heteroaryl starting materials that maybe used in the Suzuki coupling to the 2-biphenylboronic acid may beeasily prepared in a similar manner from commercially available startingmaterials.

For example, 2-bromo-5-methylthiopyridine may be prepared by thetreatment of 2-methoxy-5-bromopyridine (Shiao. M. J. et. al. Syn. Comm.20(19), 2971, 1990) with n-butyllithium in anhydrous tetrahydrofuran at-78 ° C. followed by quenching the reaction with dimethyldisulfide toafford 2-methoxy-5-methylthiopyridine. Demethylation provides2-hydroxy-5-methylthiopyridine which upon reaction withphosphorousoxybromide yields the desired 2-bromo-5-methylthiopyridinestarting material. (Scheme 7) ##STR19##

Compounds of Formula I wherein X is a single bond and R¹ is an aromaticheterocycle can be prepared by substitution of the appropriatebromoheteroaryl in place of the bromobenzene used for the Suzukicouplings described in the above Schemes. Suitable bromoheteroarylsinclude, but are not limited to, 2- or 3-bromofuran, 2- or3-bromothiophene, 3-bromopyridine, 2-bromobenzofuran (Baciocchi, E. et.al. J. Perk. Trans. II, 1976, 266) and 5-bromobenzothiophene (Worden et.al. J, Het. Chem. 25, 1271, 1988).

Compounds of Formula I wherein R⁸ is other than H can be prepared usingappropriately substituted 4-methylthiophenols as starting materials.These phenols may be prepared from commercially available startingmaterials by methods known in the art of organic synthesis. One suchpreparation is illustrated in Scheme 8, wherein3-methyl-4-methylthioanisole is selectively demethylated to afford thecorresponding phenol, which upon treatment with triflic anhydride in thepresence of 2,6-lutidine in methylene chloride (Gerlach, U. et. al. Tet.Lett. 33(38), 5499, 1992), gives a triflate suitable for use in theabove described palladium coupling procedures. The resulting methylthiointermediate can be converted into a compound of Formula I by oxidationto the corresponding sulfone as previously described. ##STR20##

Compounds of Formula 1 wherein R³ is other than hydrogen may be preparedthrough the use of appropriately substituted, commercially availablebromobenzenes as starting materials for the Suzuki couplings describedabove. Standard functional group manipulations of the resultingcompounds using methods well known to one skilled in the art of organicsynthesis will provide additional R³ substituents for which commercialstarting materials are not available. The following Schemes serve toillustrate methods for the preparation of compounds of Formula I with awide variety of R³ substituents. ##STR21##

Palladium catalysed Suzuki coupling of 3-nitro-4-bromoacetophenone withphenylboronic acid affords 3-nitro-1-acetobiphenyl. Reduction of thenitro group with tin chloride in hydrochloric acid gives an amine whichmay be converted to the diazoniumfluoroborate by treatment withiso-amylnitrite and boron trifluoride etherate in methylene chloride(Doyle, M. P. et. al., J. Org. Chem. 44, 1572, 1979). The diazonium saltcan then be converted directly to the triflate by treatment withtrifluoroacetic acid (Yoneda, N. et. al. Chem. Lett. 1991, 459).Coupling of the triflate with 4-methylthiophenyl boronic acid asdescribed above followed by oxidation with excess MCPBA(m-chloroperbenzoic acid) provides a compound of Formula I wherein R³ isOH. (Scheme 9)

This compound can serve as the starting material for further compoundsof Formula I as illustrated in Scheme 10. Conversion of the hydroxylgroup to an ether may be achieved by alkylation with sodium hydride andan appropriate alkyl halide in anhydrous tetrahydrofuran. The hydroxylgroup may also be converted to a triflate by treatment with triflicanhydride in the presence of 2,6-lutidine using methylene chloride assolvent. The resulting triflate can undergo a palladium catalysed Suzukicoupling (Cacchi et. al. Tet. Lett. 27(33), 3931, 1986; Kalinin, V.Synthesis 413, 1992) or Stille coupling (Stille, J. K. J. Am. Chem. Soc.1988, 110, 1557) to afford substituted alkenyl, keto and carboxylic acidderivatives.

In addition to the transformations shown in Scheme 10, by employingtechniques known in the art of organic synthesis, the esters may besaponified to the carboxylic acids which in turn may be converted tosubstituted amides, ketones, or hydroxamates. The alkene esters may alsobe reduced by catalytic hydrogenation to give the saturated esters usingpalladium on charcoal as catalyst. ##STR22##

Compounds of Formula I wherein R³ is an amine function, may be preparedfrom the intermediate 2-[4-methylthiophenyl]-4-aceto-1-biphenylintermediates prepared in Scheme 9 as shown in Scheme 11a. Beckmannrearrangement (Donaruma, L. G. et al., Organic Reactions, Vol 11, 1-156,1960) of the ketone followed by hydrolysis of the resulting amideprovides an amine which may then be converted to amides, disubstitutedamines or substituted amides by procedures known in the art of organicsynthesis. Oxidation of the methylthio group as previously describedgives compounds of Formula I. Alternatively compounds wherein R³ is anamino function may also be obtained from carboxylic acids via the"Curtius rearrangement" (Banthorpe, D. V. in "The Chemistry of the AzidoGroup," Palai, S. Ed., Interscience, New York, 1971, pp 397-405) asshown in Scheme 12b. ##STR23##

Compounds of Formula I wherein R³ and R⁴ are both other than hydrogenmay be obtained via various methods known in the art. One such route isdepicted in Scheme 13. ##STR24##

Conversion of 3-(4'-methylthio)phenyl-1-hydroxy-4-biphenyl (prepared asdescribed for Scheme 12) to a N,N-dimethylcarbamatecan be achieved byreaction with sodium hydride and N,N-dimethylcarbamoyl chloride inanhydrous tetrahydrofuran. Directed orthometallation (Snieckus, V.Chemical Reviews, 1990, 879) using sec-butyl lithium in anhydroustetrahydrofuran followed by quenching the resulting anion with anappropriate electrophile (e.g. methyl iodide) affords an intermediatewhich can be converted to various compounds of Formula I using methodsdescribed above or known to one skilled in the art of organic synthesis.

Compounds of Formula I wherein one or more of J, K, or L is nitrogen canbe prepared by substitution of an appropriately functionalizedheterocycle for the bromo or dibromobenzenes in the above Schemes. Forexample for the case where J is nitrogen, the synthesis of a compound ofFormula I is illustrated in Scheme 14. ##STR25##

Palladium catalysed Suzuki coupling of 2-bromo-3-hydroxypyridine with anappropriately substituted phenylboronic acid provides a2-phenyl-3-hydroxypyridine. Conversion of the hydroxy group to thetriflate under conditions previously described followed by an anhydrouspalladium catalysed Suzuki coupling with 4-methylthiophenylboronic acidaffords a 2,3-diarylpyridine. A suitable solvent for this coupling isanhydrous 1,4-dioxane. Selective oxidation of the methylthio group canbe accomplished by treatment with oxone to give compounds of Formula Iwherein J is N.

Compounds of Formula I wherein X is a single bond and R¹ is1-piperidinyl or 1-pyrrolyl can be prepared from 2-bromoaniline as shownin Scheme 15. Suzuki coupling of 2-bromoaniline with4-thiomethylphenylboronic acid using the method described above followedby condensation of the resulting 2-(4-methylthiophenyl)aniline withdibromopentane in the presence of an amine base, such as triethylamine,affords the corresponding 1-[2-(4-methylthiophenyl)phenyl]piperidine.Oxidation if the methylthio to the methylsulfonyl using methodsdescribed above provides compounds of Formula I wherein R¹ is1-piperidinyl. Alternately the starting 2-bromoaniline can be convertedto the 1-[(2-bromophenyl)phenyl]pyrrole by treatment with2,5-dimethoxytetrahydrofuran in glacial acetic acid. Suzuki coupling ofthe resulting intermediate with 4-methylthiophenylboronic acid followedby oxidation, as described above, gives the1-[2-(4-methylsulfonylphenyl)phenyl]pyrrole. ##STR26##

The compounds of this invention and their preparation can be furtherunderstood by the following procedures and examples, which exemplify butdo not constitute a limit of their invention.

EXAMPLES

All melting points are uncorrected. All reactions were conducted under anitrogen atmosphere except where otherwise noted. All commercialchemicals were used as received. Chromatography was performed with Mercksilica gel 60 (230-400 mesh). The chromatography eluents are given asratios by volume. Organic phases from solvent-solvent extractions weregenerally dried over magnesium sulfate, unless otherwise noted. Solventswere generally removed by evaporation under reduced pressure on a rotaryevaporator unless otherwise noted. Peak positions for ¹ H NMR spectraare reported as parts per million (δ downfield from the internalstandard tetramethylsilane. Abbreviations for ¹ H NMR spectra are asfollows: s=singlet, d=doublet, m=multiplet, dd=doublet of doublets. Massspectra were obtained using chemical ionization with ammonia as thereagent gas. Microanalyses were performed by Quantitative TechnologiesInc., Bound Brook, N.J.

Example 1 2-[(4-methylthio)phenyl]-1-biphenyl (method 1)

A. 4-Methylthiophenyl boronic acid:

To magnesium filings (4.3 g, 180 mmol) cooled to 0° C. was slowly addeda 1M solution of borane-tetrahydrofuran complex (600 ml, 600 mmol). Tothe resulting mixture was added dropwise a suspension of4-bromothioanisole (30 g, 148 mmol) in tetrahydrofuran (75 ml). A fewcrystals of iodine were added, and the reaction was allowed to warm toroom temperature and was stirred for 72 h. The reaction was carefullypoured onto 500 g of crushed ice. The solution was made acidic (pH 3)with 1N hydrochloric acid and allowed to sit overnight. The acidicsolution was extracted with diethyl ether. The diethyl ether wasextracted with 1N sodium hydroxide. The sodium hydroxide layer wasacidified and then extracted with diethyl ether. Evaporation of solventgave colorless crystals which were recrystallized from ethyl acetate anda small amount of water to provide 12.5 g of 4-methylthiophenyl boronicacid; ¹ H NMR (DMSO) δ7.73 (d, J=8.42 Hz, 2H), 7.21 (d, J=8.42 Hz, 2H),2.47 (s, 3H); Mass spectrum (CI, CH₄) m/z 195 (M+H⁺) ethylene glycolester).

B. 2-bromo-1-(4'-methylthiophenyl)benzene:

A mixture of 4-methylthiophenyl boronic acid (31.1 g, 185 mmol),1,2-dibromobenzene (35 g, 148 mmol), and tetrabutylammonium bromide (1g, 3.10 mmol) in ethanol (125 ml) and toluene (250 ml) was degasseal bybubbling nitrogen through the mixture for 15 minutes. 2M Sodiumcarbonate (148 ml, 296 mmol) was degasseal and added to the mixture.Tetrakis (triphenylphosphine) palladium (0.35 g, 0.303 mmol) was addedand the mixture heated to reflux for 24 h. The reaction was cooled toroom temperature and filtered to remove solids. The filtrate wasconcentrated and then diluted with water and ethyl acetate. The aqueouslayer was extracted with ethyl acetate. The organic layers were combinedand washed with brine and dried over sodium sulfate. The ethyl acetatewas concentrated and a precipitate formed. The additional precipitateformed when diethyl ether (200 ml) was added. The precipitate wasremoved via filtration and the filtrate concentrated to give a crudeoil. Purification by column chromatography on silica gel using hexane aseluant provided the desired product (25.75 g., 62%) which solidified onstanding, mp 33°-35° C.; ¹ H NMR (CDCl₃) δ7.66 (d, J=8.05 Hz, 1H),7.36-7.28 (m, 6H), 7.21 (m, 1H), 2.52 (s, 3H); Mass spectrum m/z 279.1,281.1 (M+H); Analysis for C₁₃ H₁₁ BrS: Calc'd C: 55.92%, H: 3.97%, Br:28.62%; found C: 56.24%, H: 4.04%, Br: 28.96%.

C. 2-Bromo-1-(4'-methylsulfonylphenyl)benzene:

The compound of Ex. 1, part B (5.2 g, 18.7 mmol) was dissolved indichloromethane (100ml) and cooled to 0° C. 3-Chloroperbenzoic acid (8.9g, 41.2 mmol) was added and the mixture was stirred at room temperaturefor 18 h. The reaction was diluted with dichloromethane and washedsuccessively with sodium bicarbonate, dilute sodium bisulfite, driedover sodium sulfate, filtered and concentrated. Purification bychromatography on silica gel using 7:1 hexane/ethyl acetate as eluantprovided a colorless crystals which were recrystallized(dichloromethane/hexane) to give the pure product (4.02 g, 69%), mp155°-157° C.; ¹ H NMR (CDCl₃) δ8.02 (d, J=8.42 Hz, 2H), 7.71 (d, J=6.96Hz, 1H), 7.63 (d, J=8.42 Hz, 2H), 7.43 (m, 1H), 7.32 (m, 2H), 3.13 (s,3H); IR (KBr) 1306, 1142 cm⁻¹ ; Analysis for C₁₃ H₁₁ BrO₂ S:calc'd C:50.17%, H: 3.56%, S: 10.30%; found C: 50.09%, H: 3.41%, S: 10.52%.

D. 2-[(4-methylthio)phenyl]-1-biphenyl:

2-Bromo-1-(4-methylsulfonylphenyl)benzene (4 g, 12.8 mmol), phenylboronic acid (1.72 g, 14 mmol), and tetrabutylammonium bromide (0.21 g,0.65 mmol) were dissolved in toluene (70 ml) and ethanol (35 ml) anddegassed by bubbling nitrogen through for 15 minutes. Degassed 2M sodiumcarbonate (14 ml, 28 mmol) and tetrakis (triphenylphosphine) palladium(0.074 g, 0.064 mmol) were added and the mixture was heated to refluxfor 4 h. The reaction was concentrated and diluted with water and ethylacetate. The layers were separated and the aqueous layer extracted withethyl acetate. The combined organic layers were washed with brine,dried, filtered and concentrated. Purification by column chromatographyon silica gel using 3:1 hexane/ethyl acetate as eluant andrecrystallization (dichloromethane/hexane) afforded 2.55 g (65%) of thetitle compound as colorless crystals, mp 136°-138° C.; ¹ H NMR (CDCl₃)δ7.79 (d, J=8.42 Hz, 2H), 7.47 (m, 3H), 7.42 (m, 1H), 7.34 (d, J=8.7 Hz,2H), 7.23 (m, 3H), 7.11 (m, 2H) 3.04 (s, 3H); Mass spectrum (CI, CH4)m/z 309 (M+H), 337 (M+C2H5); Analysis for C₁₉ H₁₆ O₂ S: calc'd C:74.00%, H: 5.23%, S: 10.40%; found C: 74.01%, H: 5.13%, S: 10.63%.

Example 1a 2-[(4'-methylthio)phenyl]-1-biphenyl (Method 2)

A. 2-Phenyl-1-phenoxytrifluoromethane sulfonate:

A mixture of 2-Phenylphenol (5 g, 29.4 mmol), N,N-dimethylaminopyridine(0.61 g, 4.99 mmol), and 2,6-lutidine (4.1 ml, 35.0 mmol) indichloromethane (180 ml) was cooled to -30° C. Trifluoromethanesulfonicanhydride (5.90 ml, 35.0 mmol) was added and the cooling bath wasremoved. After 1 h at room temperature the mixture was washed with 0.5NHCl, water, saturated sodium bicarbonate, brine. The mixture was dried,filtered and concentrated to afford the desired triflate (8.80 g., 99%)as a yellow oil; ¹ HNMR (CDCl₃) δ7.35-7.50 (m, 9H); Mass spectrum (CI,CH₄) m/z 303 (M+H), 331 (M+C₂ H₄).

B. 2-[(4'-methylthio)phenyl]-1-biphenyl:

2-Phenyl-1-phenoxytrifluoromethane sulfonate (13.75 g, 45.5 mmol),4-methylthio benzene boronic acid (8.4 g, 50.0 mmol), and potassiumphosphate tribasic (12.6 g, 59.0 mmol) were suspended in 1,4-dioxane anddegassed by bubbling nitrogen through for 30 minutes. Tetrakis(tri-phenylphosphine)palladium (1.30 g, 1.14 mmol) was added and themixture was heated to reflux for 24 h. The mixture was cooled, filteredand concentrated. The residue was dissolved in ethyl acetate and washedwith water and brine and dried. Purification by chromatography on silicagel using hexane as eluant and recrystallization (EtOH) afforded thedesired product (4.27 g) as white crystals, mp 42°-44° C. Concentrationof the mother liquor afforded an additional 4.98 g of product; ¹ H NMR(CDCl₃) δ7.41 (s, 4H), 7.23 (m, 3H), 7.16 (m, 2H), 7.13-7.04 (m, 4H),2.45 (s, 3H); Mass spectrum m/z 277.1 (M+H), 294.1 (M+NH₄); Analysis forC₁₉ H₁₆ S cal'd C: 82.56%, H: 5.84%, S: 11.60%; found C: 82.39%, H:5.77%, S: 11.60%.

C. 2-[4'-methylthio)phenyl]-1-biphenyl:4'-Methylthiophenyl-2-phenylbenzene (2.0 g, 7.30 mmol) was dissolved indichloromethane (60 ml) and cooled to 0° C. 3-Chloroperbenzoic acid(3.40 g, 15.9 mmol) was added and the mixture w-as stirred 3 h. Themixture was washed with sodium bicarbonate, sodium bisulfate, brine, anddried. Purification by chromatography on silica gel using 4:1hexane/ethyl acetate as eluant and recrystallization(dichloromethane/hexane) afforded the title compound (0.64 g., 28.6%) asa crystalline solid, mp 135°-137° C.; ¹ H NMR (CDCl₃) δ7.79 (d, J=8.42Hz, 2H), 7.47 (m, 3H), 7.42 (m, 1H), 7.34 (d, J=8.7 Hz, 2H), 7.23 (m,3H), 7.11 (m, 2H) 3.04 (s, 3H); Mass spectrum m/z 309 (M+H) , 326(M+NH₄); IR (KBr): 1312, 1154, 760 cm⁻¹ ; Analysis for C₁₉ H₁₆ O₂ S:calc'd C: 74.00%, H: 5.23%, S: 10.40%; found C: 74.07%, H: 5.17%, S:10.37%.

Example 109 1-Cyclohexene-2-(4'-methylsulfonylphenyl)benzene

A. 2-(4'-methylthiophenyl)-1-(1-hydroxyl-1-cyclohexyl)benzene:

2-Bromo-(4'-methylthiophenyl)benzene (3.02 g, 10.8 mmol) was dissolvedin tetrahydrofuran (35 ml), cooled to -78° C. and n-butyllithium (4.5ml, 11.3 mmol) was slowly added. The pale yellow mixture was stirred at-78° C. for 2h followed by addition of cyclohexanone (1.3 ml, 12.9mmol). The reaction was stirred for 18 h and allowed to warm to roomtemperature. The reaction was diluted with water and ethyl acetate. Theaqueous layer was extracted with ethyl acetate and the combined organiclayers were dried, filtered and concentrated. Purification bychromatography on silica gel using 6:1 hexane/ethyl acetate as eluantafforded the desired product (2.51 g., 77%) as a clear oil; ¹ H NMR(CDCl₃) δ7.58 (d, 1H), 7.36 (m, 2H), 7.27 (m, 4H), 7.04 (dd, 1H), 2.53(s, 3H), 2.34 (t, 1H), 1.83-1.10 (m, 10H), Mass spectrum (highresolution, EI/DEP) calc'd M+298.139137; found M+298.138665.

B. 1-Cyclohexene-2-(4'-methylthiophenyl)benzene:

The compound of Ex. 109, part A (2.17 g, 7.27 mmol) was dissolved intoluene (30 ml) and a catalytic amount of p-toluene sulfonic acid (0.05g) was added. The mixture was heated to reflux. After 4h the mixture wascooled and washed with sodium bicarbonate, dried, filtered andcon-centrated. Purification by chromatography on silica gel using 4:1hexane/ethyl acetate as eluant and recrystallization (methanol) affordedthe cycloalkene (1.29 g., 65%) as white crystals, mp 71°-73° C.Concentration of the mother liquor afforded 0.15 g additional product; ¹H NMR (CDCl₃) δ7.37 (d, J=8.42 Hz, 2H), 7.28 (m, 6H), 5.67 (m, 1H), 2.52(s, 3H), 2.09 (m, 2H), 1.83 (m, 2H), 1.53 (m, 4H); Analysis for C₁₉ H₂₀S: calc'd C: 81.38%, H: 7.19%, N: 11.43%; found C: 81.17%, H: 7.16%, S:11.53%.

C. 1-Cyclohexene-2-(4'-methylsulfonylphenyl)benzene:

The compound of Ex. 109, part B (1.35 g, 4.80 mmol) was suspended inmethanol (125 ml), cooled to 0° C., and Oxone™ (8.30 g, 13.0 mmol) inwater (50 ml) was added. The thick suspension was allowed to warm toroom temperature and was stirred 18 h. The mixture was diluted withwater (200 ml) and a white crystalline solid was collected. The productwas rinsed with water, dilute sodium bisulfite, and water. The productwas dried in vacuo. Purification by chromatography on silica gel using4:1 hexane/ethyl acetate as eluant and recrystallization (methanol)afforded the title compound (0.524 g.,35%) as colorless crystals, mp126°-128° C. Concentration of the mother liquor afforded an additional0.278 g of product; ¹ H NMR (CDCl₃) δ7.95 (d, J=8.42 Hz, 2H), 7.63 (d,J=8.42 Hz, 2H), 7.36-7.25 (m, 4H), 5.63 (m, 1H), 3.10 (s, 3H), 2.06 (m,2H), 1.84 (m, 2H), 1.51-1.45 (m, 4H); Analysis for C₁₉ H₂₀ O₂ S: calc'dC: 73.04%, H: 6.45%, S: 10.26%; found C: 73.22%, H: 6.47%, S: 10.46%.

Example 130 3-(4'-methylsulfonylphenyl)-4-phenylphenol

A. 3-nitro-4-phenylacetophenone:

A mixture of 4-bromo-3-nitroacetophenone (2.0 g, 8.19 mmol), phenylboronic acid (1.2 g, 9.83 mmol), and tetrabutylammonium bromide (0.13 g,0.41 mmol) in 2M sodium carbonate (35 ml), ethanol (20 ml), and toluene(65 ml) was degassed by bubbling nitrogen through for 30 minutes. Themixture was heated to reflux for 4 h. The reaction was cooled and thelayers were separated. The aqueous layer was extracted with ethylacetate and the combined organic layers were dried, filtered andconcentrated. Purification by chromatography on silica gel using 4:1Hexane/ethyl acetate as eluant afforded the desired product (1.98 g.,89%) as a yellow powder; ¹ H NMR (CDCl₃) δ8.39 (d, 1H), 8.16 (dd, 1H),7.57 (d, 1H), 7.43 (m, 3H), 7.32 (dd, 2H), 2.69 (s, 3H); Mass spectrum242.1 (M+H).

B. 3-amino-4-phenylacetophenone:

A mixture of the product of Ex. 130, part A (2.0 g, 8.29 mmol), tinchloride (8.23 g, 36.48 mmol), ethanol (30 ml) and concentratedhydrochloric acid (7 ml) was heated at reflux for 2.5 h. The reactionwas cooled to 0° C. and basified (pH 10) with 6M NaOH and extracted withethyl acetate. The extract was dried and filtered through silica gel.The filtrate was concentrated and refiltered through silica gel usingchloroform as eluant. The solvent was concentrated to give the amine(1.20 g., 69%) as a yellow powder; ¹ H NMR (CDCl₃) δ7.47 (d, 1H), 7.46(s, 3H), 7.38 (dd, 2H), 7.36 (d, 1H), 7.20 (d, 1H), 3.90 (s, 2H), 2.60(s, 3H); Mass spectrum m/z 212.1 (M+H).

C. 5-Aceto-2-phenylbenzene diazonium tetrafluoroborate:

The compound of Ex. 130, part B (0.50 g, 2.36 mmol) was dissolved indichloromethane (3 ml) and added slowly to boron trifluoride etherate indichloromethane (10 ml) at -15° C. A solution of isoamylnitrite (0.35g,2.60 mmol) in dichloromethane (3 ml) was added, the ice bath was removedand a brown precipitate formed. Pentane (20 ml) was added and themixture was re-cooled to -15° C. for 20 minutes. Filtering afforded thediazonium salt (0.76 g) as a light brown powder; ¹ H NMR (CDCl₃) 59.55(d, 1H), 8.71 (dd, 1H), 7.90 (d, 1H), 7.69 (s, 5H), 2.79 (s, 3H).

D. 5-Aceto-2-phenylbenzene trifluoromethanesulfonate:

5-Aceto-2-phenylbenzene diazonium tetrafluoroborate (1.46 g, 4.79 mmol)was slowly added to trifluoromethanesulfonic acid (10 ml) at -15° C. Themixture was heated to 50° C. for 20 minutes then poured onto ice (25 g).The aqueous layer was extracted with ethyl acetate, dried, filtered, andconcentrated. Purification by chromatography on silica gel using 4:1hexane/ethyl acetate as eluant afforded the triflate (0.428mg., 77%) asa brown syrup; ¹ H NMR (CDCl₃) δ8.04 (dd, 1H), 7.96 (d, 1H), 7.62 (d,1H), 7.48 (s, 5H), 2.67 (s, 3H); Mass spectrum m/z 345 (M+H).

E. 3-(4'-Mehylthiophenyl)-4-phenylacetophenone:

A mixture of the compound of Ex. 130, part D (1.22 g, 3.54 mmol),4-methylthiophenylboronic acid (0.71 g, 4.25 mmol), and tribasicpotassium phosphate (1.13 g, 5.32 mmol) in 1,4-dioxane was degassed bybubbling nitrogen through for 15 minutes.

Tetrakis (triphenylphosphine) palladium (0.10 g, 0. 089 mmol) was addedand the mixture was heated at reflux for 18 h. The mixture was cooled,filtered and concentrated. Purification by chromatography on silica gelusing 4:1 hexane/ethyl acetate as eluant afforded the desired product(1.02 g., 90%) as a brown syrup; ¹ H NMR (CDCl₃) δ7.99 (d, 2H), 7.53 (d,1H), 7.48 (s, 2H), 7.27 (d, s, 2H), 7.17 (dd, 2H), 7.14 (q, 3H); Massspectrum m/z 319 (M+H).

F. 3-(4-Methylsulfonylphenyl)-4-phenylphenol:

To the product of Ex. 130, part E (0.30 g, 0.942 mmol) was addedperacetic acid (10 ml) and then concentrated sulfuric acid (0.25 ml).The mixture was stirred at room temperature for 48 h. The mixture waspoured onto a mixture of ice and 20% sodium bisulfite (10 ml). Theaqueous mixture was extracted with ethyl acetate, and the organic layerswere dried, filtered and concentrated. Purification by repeatedchromatography on silica gel using 2:1 hexane/ethyl acetate as eluantafforded the title compound (0.064 g., 21%) as a white powder; ¹ H NMR(CDCl₃) δ7.79 (d, 2H), 7.35 (d, 1H), 7.34 (d, 2H), 7.21 (d, 1H), 7.19(d, 2H), 7.06 (m, 2H), 6.97 (dd, 1H), 6.90 (d, 1H), 4.96 (s, 1H), 3.05(s, 3H); High resolution mass spectrum m/z calc'd: 342.1, found:342.116391 (M+NH₄).

Example 151 1-[2-(4-methylsulfonylphenyl)phenyl]piperidine

A. 2-[(4-methylthio)phenyl]aniline:

A mixture of 2-bromoaniline (2.0 g, 11.62 mmol), 4-methylthiophenylboronic acid (2.3 g, 13.69 mmol), tetrabutylammonium bromide (0.19 g,0.58 mmol), and 2M sodium carbonate (12 ml) in 85 ml of 2:1toluene/ethanol were degassed by bubbling nitrogen through for 10minutes. Tetrakis (triphenylphosphine) palladium (54 mg, 0.047 mmol) wasadded and the mixture was heated to reflux for 5h. The reaction mixturewas cooled, concentrated, and diluted with ethyl acetate and water. Theaqueous layer was extracted with ethyl acetate and the combined organiclayers were dried (MgSO₄), filtered and concentrated. The crude productwas chromatographed (hexane/ethyl acetate) to give a solid (1.4 g, 56%).mp 70°-72° C.: NMR (CDCl₃) δ7.41-7.32 (m, 4H), 7.18-7.09 (m, 2H),6.85-6.75 (m, 2H), 3.75 (brd. m, 2H), 2.53 (s, 3H) ppm; mass spec (NH₃-CI) m/z 215.9 (M+H⁺, 100%).

Part B. 1-[2-(4-methylthiophenyl)phenyl]piperidine:

To a mixture of the product from part A (0.3 g, 1.39 mmol), ethanol (10ml), and triethylamine (0.39 ml, 2.77 mmol) was added 1,5 dibromopentane(0.29 ml, 2.08 mmol). The mixture was heated to reflux for 48h, thenconcentrated and chromatographed (hexanes) to give a pink oil (0.147 g,37%). NMR (CDCl₃) δ7.73 (d, 2H), 7.39 (d, 2H) 7.36-7.30 (m, 2H),7.15-7.10 (m, 2H), 2.87-2.85 (m, 4H), 2.62 (s, 3H), 1.55 (s, 6H); massspec (NH₃ -CI) m/z 284.2 (M+H⁺, 100%).

Part C. 1-[2-(4-methylsulfonylphenyl)phenyl]piperidine:

To a mixture of the compound of Ex. 195, part C (0.145 g, 0.512 mmol) inmethanol (15 ml), cooled to 0° C., was added Oxone™ (0.79 g, 1.28 mmol).The reaction was stirred at room temperature overnight. The reaction wasdiluted with methylene chloride and extracted. The combined organiclayers were washed with sodium bicarbonate, sodium bisulfite, brine anddried (MgSO₄). The crude product was chromatographed (hexanes/ethylacetate) and recrystallized (methylene chloride/hexanes) to give a solid(50 mg, 31%). mp 140°-140.5° C. ¹ H NMR (CDCl₃) δ7.97-7.85 (dd, 4H),7.36 (t, 1H), 7.23-7.20 (dd, 1H), 7.10-7.05 (m, 2H), 3.10 (s, 3H), 2.75(m, 4H), 1.43 (m, 6H); High resolution mass spec calc'd for C₁₈ H₂₁ NSO₂: 316.137126; found: 316.136504.

Example 153 1-[2-(4'-methylsulfonylphenyl)phenyl]pyrrole

A. 1-(2-bromophenyl)pyrrole:

A mixture of 2-bromoaniline (1.72 g, 10 mmol),2,5-dimethoxytetrahydrofuran (1.32 g, 10 mmol) and glacial acetic acid(4.5 ml) was stirred at reflux for 2 h under an atmosphere of nitrogen.The mixture was allowed to cool to room temperature. Solvent was removedunder reduced pressure and the residue was purified by flash columnchromatography (9:1 hexanes-ethyl acetate) to provide the desiredpyrrole (1.85 g., 8.33 mmol, 83.3%) as a clear liquid. ¹ HNMR (CCDl₃)δ7.70-6.35 (m, 8H); IR(KBr) 3102, 1588 cm⁻¹ ; Mass Spec m/z 221.9(M+H)⁺.

B. 1-(2-(4-Methylthiophenyl)phenyl)pyrrole:

A mixture of 1-(2-bromophenyl) pyrrole (0.666 g, 3.0 mmol),4-methylthiophenylboronic acid (0.554 g., 1.1 eq.), 2M aqueous sodiumcarbonate solution (6 ml) and toluene (30 ml) was stirred at roomtemperature under an atmosphere of nitrogen. Nitrogen gas was bubbledthrough the solution for 20 min. To this mixture was addedtetrakistriphenylphosphine palladium (100 mg, catalytic) and the mixturestirred at reflux for 4 h. The resulting mixture was allowed to cool toroom temperature and was poured into 100 ml water. The mixture wasextracted with three 100 ml portions of ethyl acetable. The combinedorganic layers were dried over anhydrous magnesium sulfate, filtered andsolvent was removed under reduced pressure. The residue was purified byflash column chromatography (29:1 hexanesethyl acetate) to provide thecoupling product as an oil (0.74 g., 2.79 mmol, 92.9%). ¹ HNMR (CDCl₃)δ7.44-6.16 (m, 12H) 2.46 (s, 3H); IR (neat): 2918, 1596 cm⁻¹ ; Mass Specm/z 266.0 (M+H)⁺.

C. 1-[2-(4-methylsulfonylphenyl)phenyl]pyrrole:

A mixture of 1-(2-(4-methylthiophenyl)phenyl)pyrrole (0.74 g., 2.788mmol), and methylene chloride (35 ml) was stirred and cooled in asalt/ice water bath under an atmosphere of nitrogen. To this was addedin one portion, 3-chloroperoxybenzoic acid (50-60% 1.924 g., >2 eq.).The solution was allowed to warm to room temperature and stirredovernight. The mixture was poured into saturated sodium bisulfitesolution and extracted with three 50 ml portions of methylene chloride.The combined organic layers were washed with saturated sodiumbicarbonate, dried over anhydrous magnesium sulfate, filtered andsolvent was removed under reduced pressure. The residue was purified byflash column chromatography (2:1 hexanes-ethyl acetate) to provide thetitle compounds as an off-white powder (0.16 g., 0.538 mmol, 19.2%). ¹HNMR (CDCl₃) δ7.88-6.15 (m, 12H) 3.06 (s, 3H); IR (KBr): 2922, 1602 cm⁻¹; Mass spec m/z 298.0 (M+H)⁺.

Example 201 1-Phenoxy-2-(4'-methylsulfonylphenyl)benzene

A. 2-(4'-methylthiophenyl)-phenol:

A mixture of 2-bromophenol (3.0 g, 17.0 mmol), 4-methylthio benzeneboronic acid (3.5 g, 20.8 mmol), and tetrabutylammonium bromide (0.28 g,0.867 mmol) in toluene (100 ml), ethanol (25 ml), and 2M sodiumcarbonate (50 ml) was degassed by bubbling nitrogen through for 30minutes. Tetrakis(triphenylphosphine)palladium (0.06 g, 0.052 mmol) wasadded and the mixture was heated to reflux for 2.5 h. The reaction wascooled to room temperature and the layers were separated. The aqueouslayer was extracted with ethyl acetate and the combined organic layerswere dried, filtered, and concentrated. Purification by chromatographyon silica gel using 4:1 hexane/ethyl acetate as eluant provided thedesired coupled product (3.03 g., 81%) as a yellow powder; ¹ H NMR(CDCl₃) δ7.42 (m, 4H), 7.25 (m, 2H), 7.01 (t, 4H), 5.13 (s, 1H), 2.57(s, 3H); Mass spectrum m/z 217 (M+H).

B. 2-(4"-nitrophenoxy)-1-(4'-methylthiophenyl)benzene:

2-(4'-Methylthiophenyl)phenol (0.4 g, 1.9 mmol) and1-fluoro-4-nitrobenzene (0.27 g, 1.94 mmol) were dissolved indimethylformamide (2 ml) and cooled to 0° C. Sodium hydride (80%dispersion in oil, 0.063 g, 2.1 mmol) was added and the mixture wasallowed to warm to room temperature and was stirred 18h. The reactionwas diluted with ethyl acetate and water. The aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith brine, dried, filtered and concentrated. Purification bychromatography on silica gel using 6:1 hexane/ethyl acetate as eluantand recrystallization (dichloromethane/hexane) afforded the product(0.59 g., 96%) as yellow crystals, mp 70°-72° C.; ¹ H NMR (CDCl₃) δ8.11(d, J=9.15 Hz, 2H), 7.51 (dd, H), 7.41-7.36 (m, 4H), 7.20 (d, J=8.42 Hz,2H), 7.14 (dd, 1H), 6.88 (d, J=9.15 Hz, 2H), 2.46 (s, 3H); IR (KBr)1514, 1342 cm⁻¹ ; Analysis for C₁₉ H₁₅ NO₃ S: calc'd C: 67.64%, H:4.48%, N: 4.15%; found C: 67.60%, H: 4.39%, N: 4.09%.

C. 2-phenoxy-1-(4'-methylthiophenyl)benzene:

A mixture of the compound of Ex. 201, part B (0.18 g, 0.53 mmol), ironpowder (0.1 g, 1.8 mmol), glacial acetic acid (0.3 ml, 5 mmol ) andethanol (10 ml ) was heated to reflux for 4 h. The reaction was cooled,filtered and concentrated in vacuo. To the crude amine was addedtetrahydrofuran (11 ml ) and the mixture was heated. Isoamyl nitrite(0.143 ml, 1.06 mmol) was added and the reaction was heated to refluxfor 4 h. The reaction was concentrated and chromatographed on silica gelusing hexane/dichloromethane as eluant to afford the desired product(0.096 g., 61%) as a yellow oil; ¹ H NMR (CDCl₃) δ7.49 (d, J=8.42 Hz,2H), 7.45 (dd, 1H), 7.30-7.19 (m, 6H), 7.05 (m, 2H) 6.94 (d, J=8.42 Hz,2H), 2,48 (s, H), Mass spectrum m/z 293 (M+H).

D. 1-Phenoxy-2-(4'-methylsulfonylphenyl)benzene:

The product of Ex. 201, part C (0.096 g, 0.35 mmol) was dissolved indichloromethane (5 ml) and cooled to 0° C. 3-Chloroperbenzoic acid (0.15g, 0.73 mmol) was added and the mixture was stirred at room temperaturefor 18 h. The reaction was diluted with dichloromethane, washedsuccessively with sodium bicarbonate, sodium bisulfite, brine and thendried, filtered and concentrated. The product was chromatographed onsilica gel using 4:1 hexane/ethyl acetate as eluant and recrystallized(dichloromethane/hexane) to afford the title compound (0.063 g., 56%),mp 130°-131° C. Concentration of the mother liquor provided anadditional 0.02 g of product; ¹ H NMR (CDCl₃) δ7.94 (d, J=8.79 Hz, 2H),7.77 (d, J=8.79 Hz, 2H), 7.46 (dd, 1H), 7.37 (m, 4H), 7.09 (m, 2H), 6.94(dd, 2H), 3.06 (s, 3H); Mass spectrum m/z 325 (M+H), 342 (M+NH₄);Analysis for C₁₉ H₁₆ O₃ calc'd: C: 70.35%, H: 4.97%, S: 9.88%; found C:70.28%, H: 4.89%, S: 9.99%.

Using the above-described techniques or variations thereon appreciatedby those of skill in the art of chemical synthesis, the compounds ofTables 1-3 (shown below) can also be prepared.

                                      TABLE 1                                     __________________________________________________________________________     ##STR27##                                                                                                             Mass                                                                          spec                                 Ex.                                mp    (M + H)                              No.                                                                              R1X             R3          R4  °C.                                                                          +                                    __________________________________________________________________________    1  Ph              H           H   135-137                                                                             326.sup.a                            2  4-FPh           H           H   164-167                                                                             327                                  3  4-MePh          H           H   131-133                                                                             340.sup.a                            4  3-MeOPh         H           H   121-122                                                                             356.sup.a                            5  4-MeOPh         H           H   141-144                                                                             339                                  6  3,4-(MeO).sub.2Ph                                                                             H           H   161-163                                                                             386.sup.a                            7  4-BrPh          H           H                                              8  3-EtOPh         H           H                                              9  4-CF.sub.3 CH.sub.2 OPh                                                                       H           H                                              10 4-MeOCH2OPh     H           H                                              11 4-MeCOOPh       H           H                                              12 4-Me.sub.2 NCOOPh                                                                             H           H                                              13 4-PhCH.sub.2 COOPh                                                                            H           H                                              14 4-PhCOOPh       H           H                                              15 4-PhCH.sub.2 OOCPh                                                                            H           H                                              16 4-NH2Ph         H           H   100-103                                                                             324                                  17 3-ClPh          H           H                                              18 4-NO.sub.2Ph    H           H                                              19 4-EtSPh         H           H                                              20 4-Me.sub.2 NPh  H           H   180-182                                                                             352                                  21 4-MeC(O)Ph      H           H                                              22 4-MeC(O)NHPh    H           H                                              23 4-PhCH.sub.2 NHPh                                                                             H           H                                              24 4-PhNHPh        H           H                                              25 4-MeONHPh       H           H                                              26 4-MeOOCNHPh     H           H                                              27 4-PhCH.sub.2 OOCNHPh                                                                          H           H                                              28 4-PhOOCNHPh     H           H                                              29 4-MeNHCONHPh    H           H                                              30 4-PhCONHPh      H           H                                              31 4-PhSO.sub.2 NHPh                                                                             H           H                                              32 4-(4-MePhSO.sub.2 NH)Ph                                                                       H           H                                              33 4-PhCH.sub.2 SO.sub.2 NHPh                                                                    H           H                                              34 4-N-pyrrolidinyl-Ph                                                                           H           H                                              35 4-N-piperidinyl-Ph                                                                            H           H                                              36 4-N-morpholinyl-Ph                                                                            H           H                                              37 4-(1-piperazinyl)-Ph                                                                          H           H                                              38 4-(4-Me-1-piperazinyl)-Ph                                                                     H           H                                              39 4-(4-benzyl-1-piperazinyl)-Ph                                                                 H           H                                              40 4-BrPh          H           H                                              41 4-CHO           H           H   176   354.sup.a                            42 4-MeOCH2Ph      H           H    88   370.sup.a                            43 4-HOCH2Ph       H           H   134   356.sup.a                            44 4-CF.sub.3Ph    H           H                                              45 3-pyridazinyl   H           H                                              46 2-benzofuranyl  H           H                                              47 5-benzothienyl  H           H   183-185                                                                             382.sup.a                            48 2-benzothienyl  H           H   165-167                                                                             382.sup.a                            49 2-naphthyl      H           H   183-184                                                                             359                                  50 5-MeO-2-naphthyl                                                                              H           H   202-204                                                                             395                                  51 3-pyridyl       H           H   190   310                                  52 2-quinolyl      H           H   148-149                                                                             360                                  53 3-quinolyl      H           H   140-141                                                                             360                                  54 6-quinolyl      H           H                                              55 2-thienyl       H           H                                              56 2-thiazolyl     H           H                                              57 3-thienyl       H           H                                              58 2-furyl         H           H                                              59 2-oxazolyl      H           H                                              60 N-methyl-2-pyrrolyl                                                                           H           H                                              61 3-isoxazolyl    H           H                                              62 3-isothiazolyl  H           H                                              63 2-benzothiazolyl                                                                              H           H                                              64 2-benzoxazolyl  H           H                                              65 3-benzindazolyl H           H                                              66 5-benzotriazolyl                                                                              H           H                                              67 3-benzoisothiazolyl                                                                           H           H                                              68 3-benzoisoxazolyl                                                                             H           H                                              69 3-isoquinolyl   H           H                                              70 1-cyclohexenyl  H           H   126-128                                                                             313                                  71 cyclohexyl      H           H   151-153                                                                             332.sup.a                            72 cyclopentyl     H           H                                              73 3-Et-cyclohexyl H           H                                              74 4-MeO-cyclohexyl                                                                              H           H                                              75 2-Cl-cyclopentyl                                                                              H           H                                              76 3-F-cyclopentyl H           H                                              77 2-HO-cyclohexyl H           H                                              78 4-FPh           4-NH.sub.2  H   168-170                                                                             359.sup.a                            79 4-FPh           5-NH.sub.2  H   157-159                                                                             359.sup.a                            80 4-FPh           4-NO.sub.2  H   170-172                                                                             389.sup.a                            81 4-FPh           5-NO.sub.2  H   214-216                                                                             389.sup.a                            82 4-FPh           4-Me        H                                              83 4-FPh           4-CF3       H                                              84 4-FPh           4-Br        H                                              85 4-FPh           4-Cl        H                                              86 4-FPh           4-CN        H                                              87 Ph              4-OH        H    74   342.sup.a                            88 4-FPh           4-OMe       5-Cl                                           89 4-FPh           4-CH.sub.2 COOMe                                                                          H                                              90 4-FPh           5-CH.sub.2 COOMe                                                                          H                                              91 4-FPh           4-COOMe     H                                              92 4-FPh           5-COOMe     H                                              93 4-FPh           4-C(O)Me    H   135   386.sup.a                            94 Ph              4-SPh       H                                              95 Ph              5-SO.sub.2 Me                                                                             H                                              96 Ph              4-CHCH.sub.2                                                                              H                                              97 Ph              4-NMe.sub.2 H                                              98 Ph              4-SO.sub.2 NH.sub.2                                                                       H                                              99 Ph              4-SO.sub.2 CF.sub.3                                                                       H                                              100                                                                              Ph              4-SO.sub.2 CH.sub.2 Ph                                                                    H                                              101                                                                              Ph              4-F         5-F                                            102                                                                              Ph              4-CONH.sub.2                                                                              H                                              103                                                                              4-FPh           4CH(Me)COOMe                                                                              H                                              104                                                                              4-FPh           4-C(O)Ph    H                                              105                                                                              Ph              5-CH(Me)OMe H                                              106                                                                              Ph              4-CH.sub.2 CH.sub.2 OPh                                                                   H                                              107                                                                              Ph              4-CH.sub.2 OCOMe                                                                          H                                              108                                                                              Ph              4-CH.sub.2 OCH.sub.2 OMe                                                                  H                                              109                                                                              Ph              H           5-CF3                                          110                                                                              Ph              4-CFH.sub.2 H                                              111                                                                              Ph              4-CH.sub.2 OH                                                                             H                                              112                                                                              Ph              4-CH.sub.2 O-cyclohexyl                                                                   H                                              113                                                                              Ph              4-CH.sub.2 OCONHMe                                                                        H                                              114                                                                              Ph              4-CH.sub.2 OCONHCH.sub.2 Ph                                                               H                                              115                                                                              Ph              4-CH.sub.2 OCO-(4-ClPh)                                                                   H                                              116                                                                              Ph              4-CH.sub.2 OCH.sub.2 F                                                                    H                                              117                                                                              Ph              4-CH.sub.2 OCH.sub.2 OCOMe                                                                H                                              118                                                                              Ph              4-CH.sub.2 OCH.sub.2 NMe.sub.2                                                            H                                              119                                                                              Ph              4-CH.sub.2 OCH.sub.2 Ph                                                                   H                                              120                                                                              Ph              4-CH.sub.2 OCH.sub.2 COMe                                                                 H                                              121                                                                              Ph              4-CH.sub.2 OCH.sub.2 COOMe                                                                H                                              123                                                                              Ph              4-CH.sub.2 OCH.sub.2 -2-thienyl                                                           H                                              124                                                                              Ph              4-CH.sub.2 OCH.sub.2 -2-pyridyl                                                           H                                              125                                                                              Ph              4-CH.sub.2 NMe.sub.2                                                                      H                                              126                                                                              Ph              4-CH.sub.2 Ph                                                                             H                                              127                                                                              Ph              4-CH.sub.2 CONH.sub.2                                                                     H                                              128                                                                              Ph              4-CH.sub.2 -2-thienyl                                                                     H                                              129                                                                              Ph              4-CH.sub.2 -2-pyrimidyl                                                                   H                                              130                                                                              Ph              4-CHCHCN    H                                              131                                                                              Ph              4-CHCHCOMe  H                                              132                                                                              Ph              4-CHCHCOOH  H                                              133                                                                              Ph              4-CHCHNO.sub.2                                                                            H                                              134                                                                              Ph              4-CHCHCH.sub.2 NMe.sub.2                                                                  H                                              135                                                                              (E)-4-FC.sub.6 H.sub.5 CHCH                                                                   H           H                                              136                                                                              2-(4-fluorophenyl)-2-methylethyl                                                              H           H                                              137                                                                              4-FC.sub.6 H.sub.5 C(CH.sub.3)CH                                                              H           H                                              138                                                                              phenylthio      H           H                                              139                                                                              benzylthio      H           H                                              140                                                                              C.sub.6 H.sub.5 CH(CH.sub.3)S                                                                 H           H                                              141                                                                              4-fluorophenoxy H           H   126-128                                                                             360                                  142                                                                              4-fluorobenzoyl H           H                                              143                                                                              cyclohexyloxy   H           H   oil   331                                  144                                                                              phenoxy         H           H   130-131                                                                             325                                  145                                                                              benzyloxy       H           H   95-97 339                                  146                                                                              3-pyridyloxy    H           H                                              147                                                                              C.sub.6 H.sub.5 C(O)CH.sub.2                                                                  H           H                                              148                                                                              phenoxymethyl   H           H                                              149                                                                              phenylmethylthio                                                                              H           H                                              150                                                                              C.sub.6 H.sub.5 C(O)CH.sub.2                                                                  H           H                                              151                                                                              1-piperdinyl    H           H     140-140.5                                                                         316                                  152                                                                              C.sub.6 H.sub.5 CC                                                                            H           H   94-96 350.sup.a                            153                                                                              1-pyrrolyl      H           H   133-135                                                                             298                                  __________________________________________________________________________     .sup.a (M + NH.sub.4) +-                                                 

                                      TABLE 2                                     __________________________________________________________________________     ##STR28##                                                                                                     Mass                                                                          Spec                                         Ex.                              (M + H)                                      No  R.sup.1 X                                                                          R.sup.2     R.sup.3                                                                          R.sup.4                                                                          mp    +                                            __________________________________________________________________________    301 4-MePh                                                                             5-MeSO.sub.2 -2-pyridyl                                                                   H  H                                                     302 4-FPh                                                                              5-MeSO.sub.2 -2-pyridyl                                                                   H  H                                                     303 Ph   2-MeSO.sub.2 -5-pyridyl                                                                   H  H  104.5-107                                                                           310                                          304 Ph   3-F-4-MeSO.sub.2Ph                                                                        H  H                                                     305 Ph   2-Cl-4-MeSO.sub.2Ph                                                                       H  H                                                     306 Ph   3-Me-4-MeSO.sub.2 Ph                                                                      H  H                                                     307 Ph   3-MeO-4-MeSO.sub.2Ph                                                                      H  H                                                     308 4-MeOPh                                                                            5-MeSO.sub.2 -2-pyridyl                                                                   H  H                                                     309 4-MeOPh                                                                            2-MeSO.sub.2 -5-pyridyl                                                                   H  H                                                     310 4-MePh                                                                             2-MeSO.sub.2 -5-pyridyl                                                                   H  H                                                     311 4-FPh                                                                              2-MeSO.sub.2 -5-pyridyl                                                                   H  H                                                     312 Ph   4-H.sub.2 NSO.sub.2Ph                                                                     H  H  183-184                                                                             310                                          __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________     ##STR29##                                                                                                        Mass                                                                          spec                                                                          (M + H)                                   Ex R.sup.1 X                                                                            R.sup.2                                                                             A              mp   +                                         __________________________________________________________________________    401                                                                              Ph     4-MeSO.sub.2 Ph                                                                     2,3-naphthyl   139-140                                                                            359                                       402                                                                              4-FPh  4-MeSO.sub.2 Ph                                                                     1,2-naphthyl                                                  403                                                                              4-FPh  4-MeSO.sub.2 Ph                                                                     1,2,3,4-tetrahydro-6,7-naphthyl                               404                                                                              4-FPh  4-MeSO.sub.2 Ph                                                                     1,2,3,4-tetrahydro-5,6-naphthyl                               405                                                                              4-FPh  4-MeSO.sub.2 Ph                                                                     5,6-benzothienyl                                              406                                                                              4-FPh  4-MeSO.sub.2 Ph                                                                     1-Me-6,5-indolyl                                              407                                                                              4-FPh  4-MeSO.sub.2 Ph                                                                     4,5-benzocycloheptyl                                          408                                                                              4-FPh  4-MeSO.sub.2 Ph                                                                     5,6-indanyl                                                   409                                                                              4-FPh  4-MeSO.sub.2 Ph                                                                     5,6-benzimidazolyl                                            410                                                                              Ph     4-MeSO.sub.2 Ph                                                                     2,3-pyridyl    126-128                                                                            310                                       411                                                                              4-FPh  4-MeSO.sub.2 Ph                                                                     2,3-pyridyl    147-148                                                                            328                                       412                                                                              4-MeOPh                                                                              4-MeSO.sub.2 Ph                                                                     2,3-pyridyl    138-139                                                                            340                                       413                                                                              4-MePh 4-MeSO.sub.2 Ph                                                                     2,3-pyridyl                                                   __________________________________________________________________________

Utility

The compounds of Formula I are inhibitors of prostaglandin synthase andtherefore have utility in the treatment of inflammatory diseases and asantipyretic agents. The prostaglandin G/H synthase inhibitory activityof the compounds of the present invention is demonstrated using assaysof prostaglandin G/H inhibition, for example using the assay describedbelow for assaying inhibitors of prostaglandin G/H synthase. Thepreferred compounds of the present invention selectively inhibit PGHS 2activity and the production of PGE2 in human monocytes, as demonstratedusing the cellular assay described below.

The compounds of Formula I have the ability to reduce pyresis in vivo,for example, as demonstrated using the animal model described below. Thecompounds of the present invention possess in vivo antiinflammatoryactivity as demonstrated using the standard animal models of acute andchronic inflammation described below. The compounds of the presentinvention also have the ability to suppress/inhibit pain in vivo, asdemonstrated using the animal model of analgesia described below.

As used herein "μg" denotes microgram, "mg" denotes milligram, "g"denotes gram, "μL" denotes microliter, "mL" denotes milliliter, "L"denotes liter, "nM" denotes nanomolar, "μM" denotes micromolar, "mM"denotes millimolar, "M" denotes molar and "nm" denotes nanometer."Sigma" stands for the Sigma-Aldrich Corp. of St. Louis, Mo.

A compound is considered to be active in the prostaglandin G/H synthaseinhibition assay described below if it inhibits prostaglandin G/Hsynthase with an IC₅₀ <300 μM. Selective PGHS-2 inhibitors show a ratioof IC₅₀ vs. PGHS-1/IC₅₀ vs. PGHS-2 that is >1.

Prostaglandin G/H Synthase Inhibition Assay

Prostaglandin G/H synthase (cyclooxygenase, PGHS, Cox) activity wasdetermined spectrophotometrically essentially as described by Kulmacz etal (reference). This assay employs the reducing substrate TMPD (4,4,4',4'-tetramethyl phenyl diamine) which upon oxidation yields an intenseblue color which can be monitored at 610 nM. The assay was adapted to a96 well microtiter dish format as described below. Test compounds wereincubated with an enzyme source either, PGHS 1 or PGHS 2, in 125 μL ofbuffer (40 uM Tris Maleate, 0.8% Tween 20, 1.2 μM heme, 0.4 mg/mlgelatin, pH 6.5) for two minutes at room temperature at which time thereaction was initiated by the addition of 125 μL of arachidonic acid inbuffer (0.1M Tris/HCl. 0.2% Tween 20, pH 8.5) to give a finalarachidonate concentration of 100 μM. The reaction plate was immediatelyplaced in a microtiter reader and readings made at 610 nm for 1.5 min at3 sec intervals. Reaction rates were calculated from the slope of thelinear portion of the absorbance versus time curve. Rates for controlsamples lacking added inhibitors were used to calculate the percentinhibition of each test compound. Results are presented as an IC₅₀ valuewhich is the concentration of added compound which causes 50% inhibitionof the control rate.

Comparison of the ability to preferentially inhibit PGHS 2 versus PGHS 1was made by a comparison of IC₅₀ values obtained against the twoisoforms of the enzyme. The ratio PGHS 1 IC₅₀ /PGHS 2 IC₅₀ is referredto as the selectivity ratio. Compounds with a greater selectivity ratioare those compounds with greater potency toward the PGHS 2 isoform ofthe enzyme.

Tables A below sets forth the activity of representative compounds ofthe present invention in the prostaglandin G/H synthase inhibition assaydescribed above. In table A the IC₅₀ values are expressed as +++=IC₅₀ of<10 μM,++=IC₅₀ of 10-50 μM, and +=IC₅₀ of 50∝300 μM (μM=micromolar).

                  TABLE A                                                         ______________________________________                                        Ex. No.      IC.sub.50 (PGHS2)                                                ______________________________________                                        1            ++                                                               2            ++                                                               3            ++                                                               4            ++                                                               5            +++                                                              6            +                                                                16           +                                                                20           ++                                                               41           ++                                                               42           +++                                                              43           +                                                                47           ++                                                               48           +++                                                              49           ++                                                               50           ++                                                               51           +                                                                52           +                                                                53           +                                                                70           ++                                                               71           ++                                                               78           +                                                                79           +                                                                80           ++                                                               81           ++                                                               87           +                                                                93           ++                                                               141          +++                                                              143          +++                                                              144          +++                                                              145          +                                                                151          ++                                                               152          +++                                                              153          +                                                                305          +                                                                312          +++                                                              401          ++                                                               410          ++                                                               411          ++                                                               412          ++                                                               ______________________________________                                    

Cellular Assay

Human peripheral blood monocytes were obtained from normal donor bloodby leukophoresis and isolated by elutriation. Monocytes were suspendingin RPMI medium at 2×10 6 cells/ml, and plated at 200 μL/well in 96 wellmicrotiter plates. Test compounds were added to the cells at appropriateconcentration in DMSO such that the final DMSO concentration was 0.5% inthe medium. Cells and compound or DMSO alone were incubated for 1 hourat 37° C. at which time cells were stimulated with 1 μg/ml LPS(Lipopolysaccharide, Salmonella typehrium, 5 mg/ml in 0.1% aqueous TEA)to induce PGHS 2 enzyme activity and prostaglandin production. Cellswere incubated for 17.5 hours at 37° C. in a 95% air 5% CO₂ environmentwhen culture supernates were removed to determine the extent ofprostaglandin E2 (PGE2) formation by EIA (PerSeptive Diagnositics). Theability of test compounds to inhibit PGE2 production by 50% compared toDMSO treated cultures is given by the IC₅₀ value and represents ameasure of potency against the PGHS 2 isozyme.

Table B below sets forth the activity of representative compounds of thepresent invention in the cellular assay described above. In table B theIC₅₀ values are expressed as +++=IC₅₀ of <10 nM, ++=IC₅₀ of 10-50 nM,and+=IC₅₀ of 51-100 nM (nM=nanomolar).

                  TABLE B                                                         ______________________________________                                        Ex. No.      IC.sub.50 (PGE2)                                                 ______________________________________                                        2            ++                                                               4            +                                                                5            ++                                                               20           ++                                                               41           +                                                                48           ++                                                               49           +                                                                81           +                                                                144          +                                                                ______________________________________                                    

Rat Antipyrexia Test

The antipyretic activity of test compounds was determined by the methoddescribed by Smith and Hambourger (J. Pharmacol. Exp. Ther., 54,346-351, (1935)). Male rats are equilibrated in test room for 7 hours onday 1 at which time food is removed and rats are dosed (s.c) with a 20%solution of Schiff's brewer's yeast (in saline) to induce fever. Acontrol group receiving saline alone is also maintained. On day 2beginning 19 hours post-dosing rat temperatures are taken and animalsare dosed either P.O., S.C., I.P, or I.V. with the appropriate doses oftest compound or vehicle. Temperatures are recorded each hour thereafterfor six hours. Pyresis is defined as the change in mean rectaltemperature between control and yeast-injected animals. Antipyreticactivity reflects the extent of mean rectal temperature loweringproduced by test compounds in those animals dosed with compound versusthose receiving vehicle alone. An ED₅₀ value is calculated as the doseof compound required to decrease pyresis by 50%.

The compounds of the present invention were tested in the above RatAntipyrexia Test and had ED50 values of ≦30mg/kg.

Rat Carrageenan Paw Edema Test

Antiinflammatory activity of test compounds was determined by the methodof Winter, C. A., Risley, E. A., and Nuss, G. W. (Proc. Soc. Exp. Biol.Med., 111, 544-547 (1962)) and briefly presented as follows. Male Lewisrats receive an injection of 0.1 ml of 1% carrageenan (in saline) intothe plantar tissue of one hind paw. Control rats are injected withsaline alone. Three hours later, paw swelling is determined as a measureof the inflammatory response. Animals are administered test compounds orvehicle either P.O., S.C., I.P., or I.V. one hour prior to footpadinjection. The decrease in hind paw swelling produced by test compoundsversus vehicle controls represents a measure of antiinflammatoryactivity. An ED₃₀ value is calculated as the dose of compound requiredto decrease the magnitude of paw swelling by 30%.

Rat Adjuvant Arthritis Test

Antiinflammatory activity was evaluated according to the methoddescribed by Pearson, C. M. (Proc. Soc. Exp. Biol. Med., 91, 95-101(1956)). Briefly, male Lewis rats received an injection of completeFreunds' adjuvant (0.1 ml of 5 mg/ml in light mineral oil) or mineraloil alone (0.1 ml) into a hind footpad. On day 18 post-injection, jointswelling is determined compared to a mineral oil injected control as ameasure of inflammation. Animals are administered compounds or vehicleeither P.O., S.C., I.P., or I.V. from day 0 to day 18. The decrease injoint swelling in dosed animals versus vehicle controls is a measure ofantiinflammatory activity. An ED₅₀ value is calculated as the dose ofcompound required to decrease the magnitude of joint swelling by 50%compared to controls.

Rat Randall Selitto Test

Analgesic activity was evaluated in the rat inflamed yeast-paw testmodified from the method of Randall, L. O. and Selitto, J. J. (Arch.Int. Pharmacodyn. Ther. 3, 409-419 (1957)) employing an Ugo Basileanalgesiometer (Stoelting). Fasted male rats were screened on both hindpaws for preyeast threshold pain response (vocalization or struggle) ofless than 15 cm slide travel on the analgesiometer. The right hind pawwas then inflamed by a subplantar injection (0.1 ml) of a 20% aqueoussuspension of Fleischmann's active dry yeast. Compounds were dosed P.O.,S.C., I.P., or I.V. 2 hours after the yeast injection. Pain reactionthresholds were determined 0.5, 1, 2, and 4 hours later. An ED₃₀ valueis calculated as the dose of compound required to increase the painthreshold by 30% compared to controls.

Dosage and Formulation

The compounds of the present invention can be administered orally usingany pharmaceutically acceptable dosage form known in the art for suchadministration. The active ingredient can be supplied in solid dosageforms such as dry powders, granules, tablets or capsules, or in liquiddosage forms, such as syrups or aqueous suspensions. The activeingredient can be administered alone, but is generally administered witha pharmaceutical carrier. A valuable treatise with respect topharmaceutical dosage forms is Remington's Pharmaceutical Sciences, MackPublishing.

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release Formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, theymay also be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form, all using dosageforms well known to those of ordinary skill in the pharmaceutical arts.An effective but non-toxic amount of the compound desired can beemployed as an antiinflammatory or antipyretic agent. The compounds ofthis invention can be administered by any means that produces contact ofthe active agent with the agent's site of action, PGHS-2, in the body ofa mammal. They can be administered by any conventional means availablefor use in conjunction with pharmaceuticals, either as individualtherapeutic agents or in a combination of therapeutic agents. They canbe administered alone, but generally administered with a pharmaceuticalcarrier selected on the basis of the chosen route of administration andstandard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient,and theeffect desired. An ordinarily skilled physician or veterinarian canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter, or arrest the progress of the condition.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. For a normal male adult human of approximately 70kg of body weight, this translates into a dosage of 70 to 1400 mg/day.Intravenously, the most preferred doses will range from about 1 to about10 mg/kg/minute during a constant rate infusion. Advantageously,compounds of the present invention may be administered in a single dailydose, or the total daily dosage may be administered in divided doses oftwo, three, or four times daily.

The compounds of the present invention can be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalroutes, using those forms of transdermal skin patches well known tothose of ordinary skill in that art. To be administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittant throughout the dosage regimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients, orcarriers (collectively referred to herein as carrier materials) suitablyselected with respect to the intended form of administration, that is,oral tablets, capsules, elixirs, syrups and the like, and consistentwith conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs, syrups, and suspensions. It can also be administeredparenterally, in sterile liquid dosage forms.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours.

Compressed tablets can be sugar coated or film coated to mask anyunpleasant taste and protect the tablet from the atmosphere, or entericcoated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance. In general, water, a suitableoil, saline, aqueous dextrose (glucose), and related sugar solutions andglycols such as propylene glycol or polyethylene glycols are suitablecarriers for parenteral solutions. Solutions for parenteraladministration preferably contain a water soluble salt of the activeingredient, suitable stabilizing agents, and if necessary, buffersubstances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field. Useful pharmaceutical dosage-forms foradministration of the compounds of this invention can be illustrated asfollows:

Capsules

Capsules are prepared by conventional procedures so that the dosage unitis 500 milligrams of active ingredient, 100 milligrams of cellulose and10 milligrams of magnesium stearate.

A large number of unit capsules may also be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

    ______________________________________                                        Syrup             Wt. %                                                       ______________________________________                                        Active Ingredient 10                                                          Liquid Sugar      50                                                          Sorbitol          20                                                          Glycerine          5                                                          Flavor, Colorant and                                                                            as required                                                 Preservative                                                                  Water             as required                                                 ______________________________________                                    

The final volume is brought up to 100% by the addition of distilledwater.

    ______________________________________                                        Aqueous Suspension     Wt. %                                                  ______________________________________                                        Active Ingredient      10                                                     Sodium Saccharin       0.01                                                   Keltrol® (Food Grade Xanthan Gum)                                                                0.2                                                    Liquid Sugar           5                                                      Flavor, Colorant and   as required                                            Preservative                                                                  Water                  as required                                            ______________________________________                                    

Xanthan gum is slowly added into distilled water before adding theactive ingredient and the rest of the Formulation ingredients. The finalsuspension is passed through a homogenizer to assure the elegance of thefinal products.

    ______________________________________                                        Resuspendable Powder  Wt. %                                                   ______________________________________                                        Active Ingredient     50.0                                                    Lactose               35.0                                                    Sugar                 10.0                                                    Acacia                4.7                                                     Sodium Carboxylmethylcellulose                                                                      0.3                                                     ______________________________________                                    

Each ingredient is finely pulverized and then uniformly mixed together.Alternatively, the powder can be prepared as a suspension and then spraydried.

    ______________________________________                                        Semi-Solid Gel    Wt. %                                                       ______________________________________                                        Active Ingredient 10                                                          Sodium Saccharin  0.02                                                        Gelatin           2                                                           Flavor, Colorant and                                                                            as required                                                 Preservative                                                                  Water             as required                                                 ______________________________________                                    

Gelatin is prepared in hot water. The finely pulverized activeingredient is suspended in the gelatin solution and then the rest of theingredients are mixed in. The suspension is filled into a suitablepackaging container and cooled down to form the gel.

    ______________________________________                                        Semi-Solid Paste    Wt. %                                                     ______________________________________                                        Active Ingredient   10                                                        Gelcarin® (Carrageenin gum)                                                                   1                                                         Sodium Saccharin    0.01                                                      Gelatin             2                                                         Flavor, Colorant and                                                                              as required                                               Preservative                                                                  Water               as required                                               ______________________________________                                    

Gelcarin® is dissolved in hot water (around 80° C.) and then thefine-powder active ingredient is suspended in this solution. Sodiumsaccharin and the rest of the Formulation ingredients are added to thesuspension while it is still warm. The suspension is homogenized andthen filled into suitable containers.

    ______________________________________                                        Emulsifiable Paste  Wt. %                                                     ______________________________________                                        Active Ingredient   30                                                        Tween® 80 and Span® 80                                                                    6                                                         Keltrol®        0.5                                                       Mineral Oil         63.5                                                      ______________________________________                                    

All the ingredients are carefully mixed together to make a homogenouspaste.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules arewashed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 500 milligrams of active ingredient, 150 milligrams of lactose,50 milligrams of cellulose and 10 milligrams of magnesium stearate.

A large number of tablets may also be prepared by conventionalprocedures so that the dosage unit was 100 milligrams of activeingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams ofmagnesium stearate, 275 milligrams of microcrystalline cellulose, 11milligrams of starch and 98.8 milligrams of lactose. Appropriatecoatings may be applied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection isprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution is made isotonic withsodium chloride and sterilized.

Suspension

An aqueous suspension is prepared for oral administration so that each 5mL contain 100 mg of finely divided active ingredient, 200 mg of sodiumcarboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitolsolution, U.S.P., and 0.025 mL of vanillin.

The compounds of the present invention may be administered incombination with a second therapeutic agent. The compound of Formula Iand such second therapeutic agent can be administered separately or as aphysical combination in a single dosage unit, in any dosage form and byvarious routes of administration, as described above.

The compound of Formula I may be Formulated together with the secondtherapeutic agent in a single dosage unit (that is, combined together inone capsule, tablet, powder, or liquid, etc.). When the compound ofFormula I and the second therapeutic agent are not Formulated togetherin a single dosage unit, the compound of Formula I and the secondtherapeutic agent may be administered essentially at the same time, orin any order; for example the compound of Formula I may be administeredfirst, followed by administration of the second agent. When notadministered at the same time, preferably the administration of thecompound of Formula I and the second therapeutic agent occurs less thanabout one hour apart, more preferably less than about 5 to 30 minutesapart.

Preferably the route of administration of the compound of Formula I isoral. Although it is preferable that the compound of Formula I and thesecond therapeutic agent are both administered by the same route (thatis, for example, both orally), if desired, they may each be administeredby different routes and in different dosage forms (that is, for example,one component of the combination product may be administered orally, andanother component may be administered intravenously). The dosage of thecompound of Formula I when administered alone or in combination with asecond therapeutic agent may vary depending upon various factors such asthe pharmacodynamic characteristics of the particular agent and its modeand route of administration, the age, health and weight of therecipient, the nature and extent of the symptoms, the kind of concurrenttreatment, the frequency of treatment, and the effect desired, asdescribed above. Particularly when provided as a single dosage unit, thepotential exists for a chemical interaction between the combined activeingredients. For this reason, when the compound of Formula I and asecond therapeutic agent are combined in a single dosage unit they areFormulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with asustained-release material which effects a sustained-release throughoutthe gastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the Formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of inflammatory diseases, whichcomprise one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of FormulaI. Such kits may further include, if desired, one or more of variousconventional pharmaceutical kit components, such as, for example,containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, mayalso be included in the kit.

In the present disclosure it should be understood that the specifiedmaterials and conditions are important in practicing the invention butthat unspecified materials and conditions are not excluded so long asthey do not prevent the benefits of the invention from being realized.

The term "consisting essentially of" where used in the presentdisclosure is intended to have its customary meaning; namely, that allspecified materials and conditions are very important in practicing theinvention but that unspecified materials and conditions are not excludedso long as they do not prevent the benefits of the invention from beingrealized.

The foregoing disclosure includes all the information deemed essentialto enable those of skill in the art to practice the claimed invention.Because the cited references may provide further useful information,however, these cited materials are hereby incorporated by reference.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations. Various equivalents, changes and modifications may be madewithout departing from the spirit and scope of this invention, and it isunderstood that such equivalent embodiments are part of this invention.

What is claimed is:
 1. A pharmaceutical composition comprising anantiinflammatory amount of a compound of Formula I: ##STR30## or apharmaceutically acceptable salt or prodrug form thereof, wherein: J, K,and L are independently CR³, CR⁴ or N;X is a single bond, --(CHR⁵)₂ --,--CH═CR⁵ --, --CR⁵ .tbd.CH--, --C.tbd.C--, --(CHR⁵)_(p) Z--,--Z(CHR⁵)_(p) --, --C(═O)CH₂, or --CH₂ C(═O)--; Z is O or S; R¹is:phenyl substituted with 0-2 R⁷, 2-naphthyl substituted with 0-2 R⁷,C₅ -C₇ cycloalkyl substituted with 0-1 R⁹, C₅ -C₇ cycloalkenyl, providedthat when R¹ is attached directly to a heteroatom, said heteroatom isnot attached to a carbon bearing a double bond in the cycloalkene ring,a 5- to 10-membered heterocyclic ring system selected from furyl,thienyl, pyrrolyl, thiazolyl, oxazolyl, N-methylpyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, 3-pyridinyl, pyridazinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl,benzotriazolyl, benzoisothiazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, or piperidinyl, said heterocyclic ring system beingsubstituted with 0-2 R⁷ ; R² is: ##STR31## Y is --CH₃ or NH₂ ; R³ is: H,F, Br, Cl, I, CN, C₁ -C₄ alkyl substituted with 0-1 R¹², C₁ -C₄haloalkyl, C₁ -C₄ alkenyl substituted with 0-1 R¹³, NO₂, NR¹⁵ R¹⁶,S(O)_(m) R¹¹, SO₂ NR^(15a) R¹⁶, --C(═O)R⁶, --COOR¹⁷, --C(═O)NR^(15a)R¹⁶, or OR¹⁸ ; R⁴ is H, F, Br, Cl, I, C₁ -C₂ alkyl, C₁ -C₂ alkoxy, C₁-C₂ haloalkyl, --CF₃, --SR^(10a), or alternately, when R³ and R⁴ aresubstituents on adjacent carbon atoms, R³ and R⁴ can be taken togetherwith the carbon atoms to which they are attached to form a 5-7 memberedcarbocyclic or heterocyclic ring system, said heterocyclic ring systemcontaining from 1-3 heteroatoms selected from N, O or S; R⁵ is C₁ -C₂alkyl, C₁ -C₂ alkoxy, or C₁ -C₂ haloalkyl; R⁶ ishydrogen, C₁ -C₆ alkylsubstituted with 0-1 R¹⁴, phenyl substituted with 0-2 R⁹, C₅ -C₇cycloalkyl substituted with 0-1 R⁹, a 5- to 10-membered heterocyclicring system selected from furyl, thienyl, thiazolyl, oxazolyl,N-methylpyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl,pyridazinyl, pyrazinyl, or pyrimidinyl, said heterocyclic ring systembeing substituted with 0-2 R⁷ ; R⁷ is a substituent on carbon that isselected from: H, F, Br, Cl, I, C₁ -C₄ alkyl, phenyl, CH₂ OH, CH₂ OCH₃,C₁ -C₄ alkoxy, C₁ -C₄ haloalkyl, --SR¹⁰, NR¹⁵ R¹⁶, --C(═O)R¹⁰, CH₂COOR¹⁷, or OR¹⁹ ; provided that when X is a single bond then R⁷ is notortho to X; R⁸ is H, F, Br, Cl, I, hydroxy, C₁ -C₄ alkyl, C₁ -C₄ alkoxy,--(CH₂)_(n) COOR¹⁷, or --CH═CHCOOR¹⁷ ; R⁹ is H, F, Br, Cl, I, hydroxy,C₁ -C₄ alkyl, or C₁ -C₄ alkoxy; R¹⁰ is H or C₁ -C₄ alkyl; R^(10a) is C₁-C₄ alkyl; R¹¹ is C₁ -C₄ alkyl, C₁ -C₂ fluoroalkyl, phenyl, or benzyl;R¹² is F, OR¹⁸, NR¹⁵ R¹⁶, phenyl substituted with 0-2 R⁹, --CN,--C(═O)R⁶, --COOR¹⁷, --C(═O)NR¹⁵ R¹⁶, or a heterocyclic ring systemselected from morpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl,pyridinyl, piperidazinyl, pyrimidinyl, pyrazinyl, ortetrahydropyridinyl, said heterocyclic ring system being substitutedwith 0-2 R⁹ ; R¹³ is --CN, --C(═O)R⁶, --COOR¹⁷, --NO₂, or NR¹⁵ R¹⁶ ; R¹⁴is F, OH, C₁ -C₄ alkoxy, NH₂, phenyl substituted with 0-2 R⁹,alkylcarbonyl, arylcarbonyl, --COOR¹⁷, or --C(═O)NH₂ ; R¹⁵ is H, C₁ -C₄alkyl substituted with 0-1 R²³, C₆ -C₁₀ aryl, C₃ -C₇ cycloalkyl, C₄ -C₁₁cycloalkylalkyl, C₂ -C₄ alkenyl, C₁ -C₄ alkoxy, C₁ -C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, C₇ -C₁₄ arylalkoxycarbonyl, C₆ -C₁₀ aryloxycarbonyl,C₁ -C₆ alkylaminocarbonyl, C₆ -C₁₀ arylcarbonyl, C₁ -C₆ alkylsulfonyl,C₆ -C₁₀ arylsulfonyl, C₇ -C₁₄ alkylarylsulfonyl, C₇ -C₁₄arylalkylsulfonyl; R^(15a) is H, C₁ -C₄ alkyl substituted with 0-1 R²³,C₆ -C₁₀ aryl, C₃ -C₇ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₂ -C₄alkenyl, C₁ -C₄ alkoxy; R¹⁶ is H, or C₁ -C₄ alkyl; alternately, R¹⁵ andR¹⁶ can be taken together to be --(CH₂)₄ --, --(CH₂)₅ --, --(CH₂)₂O(CH₂)₂ --, or --(CH₂)₂ NR²¹ (CH₂)₂ --, R¹⁷ is C₁ -C₄ alkyl, orarylalkyl; R¹⁸ is C₁ -C₄ alkyl substituted with 0-2 R²⁴, C₆ -C₁₀ aryl,C₃ -C₇ cycloalkyl, C₁ -C₆ alkylcarbonyl, C₁ -C₆ alkylaminocarbonyl, C₇-C₁₄ arylalkylcarbonyl, or C₆ -C₁₀ arylcarbonyl substituted with 0-2 R⁹; R¹⁹ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₁ -C₄ alkoxyalkyl, C₁ -C₆alkylcarbonyl, C₁ -C₆ alkylaminocarbonyl, C₇ -C₁₄ arylalkylcarbonyl, orC₆ -C₁₀ arylcarbonyl substituted with 0-2 R⁹ ; R²¹ is C₁ -C₄ alkyl orbenzyl; R²³ is H, F, phenyl substituted with 0-2 R⁹, --C(═O)R⁶,--COOR¹⁷, --C(═O)NHR¹⁶, or a heterocyclic ring system selected frommorpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl, ortetrahydropyridinyl, said heterocyclic ring system being substitutedwith 0-2 R⁹ ; R²⁴ is H, F, NR¹⁵ R¹⁶, phenyl substituted with 0-2 R⁹, C₁-C₄ alkoxy, C₁ -C₄ alkylcarbonyloxy, C(═O)R⁶, --COOR¹⁷, --C(═O)NR¹⁵ R¹⁶,or a heterocyclic ring system selected from morpholinyl, piperidinyl,pyrrolidinyl, furyl, thienyl, piperidinyl, or tetrahydropyridinyl, saidheterocyclic ring system being substituted with 0-2 R⁹ ; m is 0-2; p is0-1; provided that when J and L are both nitrogen and K is CR⁴, then R⁴cannot be SR¹⁰ ; and a pharmaceutically acceptable carrier.
 2. Apharmaceutical composition comprising an antiinflammatory amount of acompound of claim 1 or a pharmaceutically acceptable salt or prodrugform thereof, wherein:J is CH or N; Each of K and L independently is CR³or CR⁴ ; X is a single bond, (i.e. X is absent), --C.tbd.C--, or--(CHR⁵)_(p) Z--; R³ is: H, F, Br, CN, C₁ -C₄ alkyl substituted with 0-1R¹², C₁ -C₄ haloalkyl, NO₂, SO_(m) R¹¹, --C(═O)R⁶, or OR¹⁸ ; R⁴ is H, F,CH₃, or alternately, when R³ and R⁴ are substituents on adjacent carbonatoms, R³ and R⁴ can be taken together with the carbon atoms to whichthey are attached to form a 5-7 membered carbocyclic ring system; R⁶ishydrogen, C₁ -C₆ alkyl substituted with 0-1 R¹⁴, or phenyl substitutedwith 0-2 R⁹ ; R⁷ is a substituent on carbon that is selected from: H, F,Br, C₁ -C₄ alkyl, CH₂ OH, CH₂ OCH₃, C₁ -C₄ alkoxy, C₁ -C₄ haloalkyl,NR¹⁵ R¹⁶, or --C(═O)R¹⁰ ; and a pharmaceutically acceptable carrier. 3.A pharmaceutical composition comprising an antiinflammatory amount of acompound of claim 2 or a pharmaceutically acceptable salt or prodrugform thereof, wherein:R⁸ is H; R⁹ is H; R¹² is F, OR¹⁸, CN, --COOR¹⁷ ;R¹⁴ is H; R¹⁵ is H, or C₁ -C₄ alkyl; R¹⁶ is H or C₁ -C₄ alkyl; R¹⁸ is Hor C₁ -C₄ alkyl; R¹⁹ is C₁ -C₄ alkyl; and a pharmaceutically acceptablecarrier.
 4. A pharmaceutical composition comprising an antiinflammatoryamount of a compound of claim 1 of Formula Ia: ##STR32## wherein: R¹ Xis phenyl, 4-fluorophenyl, 3-methoxyphenyl, 4-methoxyphenyl,3,4-dimethoxyphenyl, 4-hydroxymethylphenyl, 4-methoxymethylphenyl,4-dimethylaminophenyl, 4-formylphenyl, 2-naphthyl, 5-methoxy-2-naphthyl,2-quinolinyl, 3-quinolinyl, 2-benzothienyl, 5-benzothienyl, 3-pyridyl,phenylacetylenyl, phenoxy, cyclohexenyl, cyclohexyl, 4-fluorophenoxy,cyclohexyloxy, benzyloxy, 1-pyrrolyl or 1-piperidinyl;R³ is hydrogen,4-hydroxy, 4-nitro, 5-nitro or 4-aceto; and a pharmaceuticallyacceptable carrier.
 5. A pharmaceutical composition comprising anantiinflammatory amount of a compound of claim 4 or a pharmaceuticallyacceptable salt or prodrug form thereof, wherein:R¹ X is phenyl; and R³is hydrogen, 4-hydroxy, 4-nitro, 5-nitro or 4-aceto; or R¹ X is4-fluorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl,4-hydroxymethylphenyl, 4-methoxymethylphenyl, 4-dimethylaminophenyl,4-formylphenyl, 2-naphthyl, 5-methoxy-2-naphthyl, 2-quinolinyl,3-quinolinyl, 2-benzothienyl, 5-benzothienyl, 3-pyridyl,phenylacetylenyl, phenoxy, cyclohexenyl, cyclohexyl, 4-fluorophenoxy,cyclohexyloxy, benzyloxy, 1-pyrrolyl or 1-piperdinyl; and R³ ishydrogen; and a pharmaceutically acceptable carrier.
 6. A pharmaceuticalcomposition comprising an antiinflammatory amount of a compound of claim1 selected from the group consistingof:2-(4-methylsulfonylphenyl)-3-phenylnaphthalene,3-(4-methylsulfonylphenyl)-2-phenylpyridine, and2-(4-aminosulfonylphenyl)-1-biphenyl; anda pharmaceutically acceptablecarrier.
 7. A method of inhibiting prostaglandin H synthase in a mammalcomprising administering to the mammal an effective amount of a compoundof Formula I: ##STR33## or a pharmaceutically acceptable salt or prodrugform thereof, wherein: J, K, and L are independently CR³, CR⁴ or N;X isa single bond, (i.e. X is absent), --(CHR⁵)₂ --, --CH═CR⁵ --, --CR⁵═CH--, --C.tbd.C--, --(CHR⁵)_(p) Z--, --Z (CHR⁵)_(p) --, --C(═O)CH₂, or--CH₂ C(═O)--; Z is O or S; R¹ is:phenyl substituted with 0-2 R⁷,2-naphthyl substituted with 0-2 R⁷, C₅ -C₇ cycloalkyl substituted with0-1 R⁹, C₅ -C₇ cycloalkenyl, provided that when R¹ is attached directlyto a heteroatom, said heteroatom is not attached to a carbon bearing adouble bond in the cycloalkene ring, a 5- to 10-membered heterocyclicring system selected from furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl,N-methylpyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, 3-pyridinyl,pyridazinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzoxazolyl, benzotriazolyl, benzoisothiazolyl,benzisoxazolyl, quinolinyl, isoquinolinyl, or piperidinyl, saidheterocyclic ring system being substituted with 0-2 R⁷ ; R² is:##STR34## Y is --CH₃ or NH₂ ; R³ is: H, F, Br, Cl, I, CN, C₁ -C₄ alkylsubstituted with 0-1 R¹², C₁ -C₄ haloalkyl, C₁ -C₄ alkenyl substitutedwith 0-1 R¹³, NO₂, NR¹⁵ R¹⁶, S(O)_(m) R¹¹, SO₂ NR^(15a) R¹⁶, --C(═O)R⁶,--COOR¹⁷, --C(═O)NR^(15a) R¹⁶, or OR¹⁸ ; R⁴ is H, F, Br, Cl, I, C₁ -C₂alkyl, C₁ -C₂ alkoxy, C₁ -C₂ haloalkyl, --CF₃, --SR^(10a), oralternately, when R³ and R⁴ are substituents on adjacent carbon atoms,R³ and R⁴ can be taken together with the carbon atoms to which they areattached to form a 5-7 membered carbocyclic or heterocyclic ring system,said heterocyclic ring system containing from 1-3 heteroatoms selectedfrom N, O or S; R⁵ is C₁ -C₂ alkyl, C₁ -C₂ alkoxy, or C₁ -C₂ haloalkyl;R⁶ ishydrogen, C₁ -C₆ alkyl substituted with 0-1 R¹⁴, phenyl substitutedwith 0-2 R⁹, C₅ -C₇ cycloalkyl substituted with 0-1 R⁹, a 5- to10-membered heterocyclic ring system selected from furyl, thienyl,thiazolyl, oxazolyl, N-methylpyrrolyl, isoxazolyl, isothiazolyl,pyrazolyl, pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl, saidheterocyclic ring system being substituted with 0-2 R⁷ ; R⁷ is asubstituent on carbon that is selected from: H, F, Br, Cl, I, C₁ -C₄alkyl, phenyl, CH₂ OH, CH₂ OCH₃, C₁ -C₄ alkoxy, C₁ -C₄ haloalkyl,--SR¹⁰, NR¹⁵ R¹⁶, --C(═O)R¹⁰, CH₂ COOR¹⁷, or OR¹⁹ ; provided that when Xis a single bond then R⁷ is not ortho to X; R⁸ is H, F, Br, Cl, I,hydroxy, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, --(CH₂)_(n) COOR¹⁷, or--CH═CHCOOR¹⁷ ; R⁹ is H, F, Br, Cl, I, hydroxy, C₁ -C₄ alkyl, or C₁ -C₄alkoxy; R¹⁰ is H or C₁ -C₄ alkyl; R^(10a) is C₁ -C₄ alkyl; R¹¹ is C₁ -C₄alkyl, C₁ -C₂ fluoroalkyl, phenyl, or benzyl; R¹² is F, OR¹⁸, NR¹⁵ R¹⁶,phenyl substituted with 0-2 R⁹, --CN, --C(═O)R⁶, --COOR¹⁷, --C(═O)NR¹⁵R¹⁶, or a heterocyclic ring system selected from morpholinyl,piperidinyl, pyrrolidinyl, furyl, thienyl, pyridinyl, piperidazinyl,pyrimidinyl, pyrazinyl, or tetrahydropyridinyl, said heterocyclic ringsystem being substituted with 0-2 R⁹ ; R¹³ is --CN, --C(═O)R⁶, --COOR¹⁷,--NO₂, or NR¹⁵ R¹⁶ ; R¹⁴ is F, OH, C₁ -C₄ alkoxy, NH₂, phenylsubstituted with 0-2 R⁹, alkylcarbonyl, arylcarbonyl, --COOR¹⁷, or--C(═O)NH₂ ; R¹⁵ is H, C₁ -C₄ alkyl substituted with 0-1 R²³, C₆ -C₁₀aryl, C₃ -C₇ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₂ -C₄ alkenyl, C₁ -C₄alkoxy, C₁ -C₆ alkylcarbonyl, C₁ -C₆ alkoxycarbonyl, C₇ -C₁₄arylalkoxycarbonyl, C₆ -C₁₀ aryloxycarbonyl, C₁ -C₆ alkylaminocarbonyl,C₆ -C₁₀ arylcarbonyl, C₁ -C₆ alkylsulfonyl, C₆ -C₁₀ arylsulfonyl, C₇-C₁₄ alkylarylsulfonyl, C₇ -C₁₄ arylalkylsulfonyl; R^(15a) is H, C₁ -C₄alkyl substituted with 0-1 R²³, C₆ -C₁₀ aryl, C₃ -C₇ cycloalkyl, C₄ -C₁₁cycloalkylalkyl, C₂ -C₄ alkenyl, C₁ -C₄ alkoxy; R¹⁶ is H, or C₁ -C₄alkyl; alternately, R¹⁵ and R¹⁶ can be taken together to be --(CH₂)₄ --,--(CH₂)₅ --, --(CH₂)₂ O(CH₂)₂ --, or --(CH₂)₂ NR²¹ (CH₂)₂ --, R¹⁷ is C₁-C₄ alkyl, or arylalkyl; R¹⁸ is C₁ -C₄ alkyl substituted with 0-2 R²⁴,C₆ -C₁₀ aryl, C₃ -C₇ cycloalkyl, C₁ -C₆ alkylcarbonyl, C₁ -C₆alkylaminocarbonyl, C₇ -C₁₄ arylalkylcarbonyl, or C₆ -C₁₀ arylcarbonylsubstituted with 0-2 R⁹ ; R¹⁹ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₁ -C₄alkoxyalkyl, C₁ -C₆ alkylcarbonyl, C₁ -C₆ alkylaminocarbonyl, C₇ -C₁₄arylalkylcarbonyl, or C₆ -C₁₀ arylcarbonyl substituted with 0-2 R⁹ ; R²¹is C₁ -C₄ alkyl or benzyl; R²³ is H, F, phenyl substituted with 0-2 R⁹,--C(═O)R⁶, --COOR¹⁷, --C(═O)NHR¹⁶, or a heterocyclic ring systemselected from morpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl, ortetrahydropyridinyl, said heterocyclic ring system being substitutedwith 0-2 R⁹ ; R²⁴ is H, F, NR¹⁵ R¹⁶, phenyl substituted with 0-2 R⁹, C₁-C₄ alkoxy, C₁ -C₄ alkylcarbonyloxy, C(═O)R⁶, --COOR¹⁷, --C(═O)NR¹⁵ R¹⁶,or a heterocyclic ring system selected from morpholinyl, piperidinyl,pyrrolidinyl, furyl, thienyl, piperidinyl, or tetrahydropyridinyl, saidheterocyclic ring system being substituted with 0-2 R⁹ ; m is 0-2; p is0-1;provided that when J and L are both nitrogen and K is CR⁴, then R⁴cannot be SR¹⁰.
 8. A method of inhibiting prostaglandin H synthase in amammal comprising administering to the mammal an effective amount of acompound of claim 7 selected from the group consistingof:2-(4-methylsulfonylphenyl)-3-phenylnaphthalene,3-(4-methylsulfonylphenyl)-2-phenylpyridine, and2-(4-aminosulfonylphenyl)-1-biphenyl.
 9. A method of treating aninflammatory disease in a mammal comprising administering to the mammalin need of such treatment a therapeutically effective amount of acompound of Formula I: ##STR35## or a pharmaceutically acceptable saltor prodrug form thereof, wherein: J, K, and L are independently CR³, CR⁴or N;X is a single bond, (i.e. X is absent), --(CHR⁵)₂ --, --CH═CR⁵ --,--CR⁵ ═CH--, --C.tbd.C--, --(CHR⁵)_(p) Z--, --Z(CHR⁵)_(p) --,--C(═O)CH₂, or --CH₂ C(═O)--; Z is O or S; R¹ is:phenyl substituted with0-2 R⁷, 2-naphthyl substituted with 0-2 R⁷, C₅ -C₇ cycloalkylsubstituted with 0-1 R⁹, C₅ -C₇ cycloalkenyl, provided that when R¹ isattached directly to a heteroatom, said heteroatom is not attached to acarbon bearing a double bond in the cycloalkene ring, a 5- to10-membered heterocyclic ring system selected from furyl, thienyl,pyrrolyl, thiazolyl, oxazolyl, N-methylpyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, 3-pyridinyl, pyridazinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl,benzotriazolyl, benzoisothiazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, or piperidinyl, said heterocyclic ring system beingsubstituted with 0-2 R⁷ ; R² is: ##STR36## Y is --CH₃ or NH₂ ; R³ is: H,F, Br, Cl, I, CN, C₁ -C₄ alkyl substituted with 0-1 R¹², C₁ -C₄haloalkyl, C₁ -C₄ alkenyl substituted with 0-1 R¹³, NO₂, NR¹⁵ R¹⁶,S(O)_(m) R¹¹, SO₂ NR^(15a) R¹⁶, --C(═O)R⁶, --COOR¹⁷, --C(═O)NR^(15a)R¹⁶, or OR¹⁸ ; R⁴ is H, F, Br, Cl, I, C₁ -C₂ alkyl, C₁ -C₂ alkoxy, C₁-C₂ haloalkyl, --CF₃, --SR^(10a), or alternately, when R³ and R⁴ aresubstituents on adjacent carbon atoms, R³ and R⁴ can be taken togetherwith the carbon atoms to which they are attached to form a 5-7 memberedcarbocyclic or heterocyclic ring system, said heterocyclic ring systemcontaining from 1-3 heteroatoms selected from N, O or S; R⁵ is C₁ -C₂alkyl, C₁ -C₂ alkoxy, or C₁ -C₂ haloalkyl; R⁶ ishydrogen, C₁ -C₆ alkylsubstituted with 0-1 R¹⁴, phenyl substituted with 0-2 R⁹, C₅ -C₇cycloalkyl substituted with 0-1 R⁹, a 5- to 10-membered heterocyclicring system selected from furyl, thienyl, thiazolyl, oxazolyl,N-methylpyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl,pyridazinyl, pyrazinyl, or pyrimidinyl, said heterocyclic ring systembeing substituted with 0-2 R⁷ ; R⁷ is a substituent on carbon that isselected from: H, F, Br, Cl, I, C_(1`-C) ₄ alkyl, phenyl, CH₂ OH, CH₂OCH₃, C₁ -C₄ alkoxy, C₁ -C₄ haloalkyl, --SR¹⁰, NR¹⁵ R¹⁶, --C(═O)R¹⁰, CH₂COOR¹⁷, OR¹⁹ ; provided that when X is a single bond then R⁷ is notortho to X; R⁸ is H, F, Br, Cl, I, hydroxy, C₁ -C₄ alkyl, C₁ -C₄ alkoxy,--(CH₂)_(n) COOR¹⁷, or --CH═CHCOOR¹⁷ ; R⁹ is H, F, Br, Cl, I, hydroxy,C₁ -C₄ alkyl, or C₁ -C₄ alkoxy; R¹⁰ is H or C₁ -C₄ alkyl; R^(10a) is C₁-C₄ alkyl; R¹¹ is C₁ -C₄ alkyl, C₁ -C₂ fluoroalkyl, phenyl, or benzyl;R¹² is F, OR¹⁸, NR¹⁵ R¹⁶, phenyl substituted with 0-2 R⁹, --CN,--C(═O)R⁶, --COOR¹⁷, --C(═O)NR¹⁵ R¹⁶, or a heterocyclic ring systemselected from morpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl,pyridinyl, piperidazinyl, pyrimidinyl, pyrazinyl, ortetrahydropyridinyl, said heterocyclic ring system being substitutedwith 0-2 R⁹ ; R¹³ is --CN, --C(═O)R⁶, --COOR¹⁷, --NO₂, or NR¹⁵ R¹⁶ ; R¹⁴is F, OH, C₁ -C₄ alkoxy, NH₂, phenyl substituted with 0-2 R⁹,alkylcarbonyl, arylcarbonyl, --COOR¹⁷, or --C(═O)NH₂ ; R¹⁵ is H, C₁ -C₄alkyl substituted with 0-1 R²³, C₆ -C₁₀ aryl, C₃ -C₇ cycloalkyl, C₄ -C₁₁cycloalkylalkyl, C₂ -C₄ alkenyl, C₁ -C₄ alkoxy, C₁ -C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, C₇ -C₁₄ arylalkoxycarbonyl, C₆ -C₁₀ aryloxycarbonyl,C₁ -C₆ alkylaminocarbonyl, C₆ -C₁₀ arylcarbonyl, C₁ -C₆ alkylsulfonyl,C₆ -C₁₀ arylsulfonyl, C₇ -C₁₄ alkylarylsulfonyl, C₇ -C₁₄arylalkylsulfonyl; R^(15a) is H, C₁ -C₄ alkyl substituted with 0-1 R²³,C₆ -C₁₀ aryl, C₃ -C₇ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₂ -C₄alkenyl, C₁ -C₄ alkoxy; R¹⁶ is H, or C₁ -C₄ alkyl; alternately, R¹⁵ andR¹⁶ can be taken together to be --(CH₂)₄ --, --(CH₂)₅ --, --(CH₂)₂O(CH₂)₂ --, or --(CH₂)₂ NR²¹ (CH₂)₂ --, R¹⁷ is C₁ -C₄ alkyl, orarylalkyl; R¹⁸ is C₁ -C₄ alkyl substituted with 0-2 R²⁴, C₆ -C₁₀ aryl,C₃ -C₇ cycloalkyl, C₁ -C₆ alkylcarbonyl, C₁ -C₆ alkylaminocarbonyl, C₇-C₁₄ arylalkylcarbonyl, or C₆ -C₁₀ arylcarbonyl substituted with 0-2 R⁹; R¹⁹ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₁ -C₄ alkoxyalkyl, C₁ -C₆alkylcarbonyl, C₁ -C₆ alkylaminocarbonyl, C₇ -C₁₄ arylalkylcarbonyl, orC₆ -C₁₀ arylcarbonyl substituted with 0-2 R⁹ ; R²¹ is C₁ -C₄ alkyl orbenzyl; R²³ is H, F, phenyl substituted with 0-2 R⁹, --C(═O)R⁶,--COOR¹⁷, --C(═O)NHR¹⁶, or a heterocyclic ring system selected frommorpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl, ortetrahydropyridinyl, said heterocyclic ring system being substitutedwith 0-2 R⁹ ; R²⁴ is H, F, NR¹⁵ R¹⁶, phenyl substituted with 0-2 R⁹, C₁-C₄ alkoxy, C₁ -C₄ alkylcarbonyloxy, C(═O)R⁶, --COOR¹⁷, --C(═O)NR¹⁵ R¹⁶,or a heterocyclic ring system selected from morpholinyl, piperidinyl,pyrrolidinyl, furyl, thienyl, piperidinyl, or tetrahydropyridinyl, saidheterocyclic ring system being substituted with 0-2 R⁹ ; m is 0-2; p is0-1;provided that when J and L are both nitrogen and K is CR⁴ then R⁴cannot be SR¹⁰.
 10. A method of treating an inflammatory disease in amammal comprising administering to the mammal in need of such treatmenta therapeutically effective amount of a compound of claim 9 selectedfrom the group consistingof:2-(4-methylsulfonylphenyl)-3-phenylnaphthalene,3-(4-methylsulfonylphenyl)-2-phenylpyridine, and2-(4-aminosulfonylphenyl)-1-biphenyl.
 11. A method of treating pyresisin a mammal comprising administering to the mammal in need of suchtreatment a therapeutically effective amount of a compound of Formula I:##STR37## or a pharmaceutically acceptable salt or prodrug form thereof,wherein: J, K, and L are independently CR³, CR⁴ or N;X is a single bond,(i.e. X is absent), --(CHR⁵)₂ --, --CH═CR⁵ --, --CR⁵ ═CH--, --C.tbd.C--,--(CHR⁵)_(p) Z--, --Z(CHR⁵)_(p) --, --C(═O)CH₂, or --CH₂ C(═O)--; Z is Oor S; R¹ is:phenyl substituted with 0-2 R⁷, 2-naphthyl substituted with0-2 R⁷, C₅ -C₇ cycloalkyl substituted with 0-1 R⁹, C₅ -C₇ cycloalkenyl,provided that when R¹ is attached directly to a heteroatom, saidheteroatom is not attached to a carbon bearing a double bond in thecycloalkene ring, a 5- to 10-membered heterocyclic ring system selectedfrom furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, N-methylpyrrolyl,isoxazolyl, isothiazolyl, pyrazolyl, 3-pyridinyl, pyridazinyl,pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl,benzoxazolyl, benzotriazolyl, benzoisothiazolyl, benzisoxazolyl,quinolinyl, isoquinolinyl, or piperidinyl, said heterocyclic ring systembeing substituted with 0-2 R⁷ ; R² is: ##STR38## Y is --CH₃ or NH² ; R³is: H, F, Br, Cl, I, CN, C₁ -C₄ alkyl substituted with 0-1 R¹², C₁ -C₄haloalkyl, C₁ -C₄ alkenyl substituted with 0-1 R¹³, NO₂, NR¹⁵ R¹⁶,S(O)_(m) R¹¹, SO₂ NR^(15a) R¹⁶, --C(═O)R⁶, --COOR¹⁷, --C(═O)NR^(15a)R¹⁶, or OR¹⁸ ; R⁴ is H, F, Br, Cl, I, C₁ -C₂ alkyl, C₁ -C₂ alkoxy, C₁-C₂ haloalkyl, --CF₃, --SR^(10a), or alternately, when R³ and R⁴ aresubstituents on adjacent carbon atoms, R³ and R⁴ can be taken togetherwith the carbon atoms to which they are attached to form a 5-7 memberedcarbocyclic or heterocyclic ring system, said heterocyclic ring systemcontaining from 1-3 heteroatoms selected from N, O or S; R⁵ is C₁ -C₂alkyl, C₁ -C₂ alkoxy, or C₁ -C₂ haloalkyl; R⁶ ishydrogen, C₁ -C₆ alkylsubstituted with 0-1 R¹⁴, phenyl substituted with 0-2 R⁹, C₅ -C₇cycloalkyl substituted with 0-1 R⁹, a 5- to 10-membered heterocyclicring system selected from furyl, thienyl, thiazolyl, oxazolyl,N-methylpyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridinyl,pyridazinyl, pyrazinyl, or pyrimidinyl, said heterocyclic ring systembeing substituted with 0-2 R⁷ ; R⁷ is a substituent on carbon that isselected from: H, F, Br, Cl, I, C₁ -C₄ alkyl, phenyl, CH₂ OH, CH₂ OCH₃,C₁ -C₄ alkyoxy, C₁ -C₄ haloalkyl, --SR¹⁰, NR¹⁵ R¹⁶, --C(═O)R¹⁰, CH₂COOR¹⁷, or OR¹⁹ ; provided that when X is a single bond then R⁷ is notortho to X; R⁸ is H, F, Br, Cl, I, hydroxy, C₁ -C₄ alkyl, C₁ -C₄ alkoxy,--(CH₂)_(n) COOR¹⁷, or --CH═CHCOOR¹⁷ ; R⁹ is H, F, Br, Cl, I, hydroxy,C₁ -C₄ alkyl, or C₁ -C₄ alkoxy; R¹⁰ is H or C₁ -C₄ alkyl; R^(10a) is C₁-C₄ alkyl; R¹¹ is C₁ -C₄ alkyl, C₁ -C₂ fluoroalkyl, phenyl, or benzyl;R¹² is F, OR¹⁸, NR¹⁵ R¹⁶, phenyl substituted with 0-2 R⁹, --CN,--C(═O)R⁶, --COOR¹⁷, --C(═O)NR¹⁵ R¹⁶, or a heterocyclic ring systemselected from morpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl,pyridinyl, piperidazinyl, pyrimidinyl, pyrazinyl, ortetrahydropyridinyl, said heterocyclic ring system being substitutedwith 0-2 R⁹ ; R¹³ is --CN, --C(═O)R⁶, --COOR¹⁷, --NO², or NR¹⁵ R¹⁶ ; R¹⁴is F, OH, C₁ -C₄ alkoxy, NH₂, phenyl substituted with 0-2 R⁹,alkylcarbonyl, arylcarbonyl, --COOR¹⁷, or --C(═O)NH² ; R¹⁵ is H, C₁ -C₄alkyl substituted with 0-1 R²³, C₆ -C₁₀ aryl, C₃ -C₇ cycloalkyl, C₄ -C₁₁cycloalkylalkyl, C₂ -C₄ alkenyl, C₁ -C₄ alkoxy, C₁ -C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, C₇ -C₁₄ arylalkoxycarbonyl, C₆ -C₁₀ aryloxycarbonyl,C₁ -C₆ alkylaminocarbonyl, C₆ -C₁₀ arylcarbonyl, C₁ -C₆ alkylsulfonyl,C₆ -C₁₀ arylsulfonyl, C₇ -C₁₄ alkylarylsulfonyl, C₇ -C₁₄arylalkylsulfonyl; R^(15a) is H, C₁ -C₄ alkyl substituted with 0-1 R²³,C₆ -C₁₀ aryl, C₃ -C₇ cycloalkyl, C₄ -C₁₁ cycloalkylalkyl, C₂ -C₄alkenyl, C₁ -C₄ alkoxy; R¹⁶ is H, or C₁ -C₄ alkyl; alternately, R¹⁵ andR¹⁶ can be taken together to be --(CH₂)₄ --, --(CH₂)₅ --, --(CH₂)₂O(CH₂)₂ --, or --(CH₂)₂ NR²¹ (CH₂)₂ --, R¹⁷ is C₁ -C₄ alkyl, orarylalkyl; R¹⁸ is C₁ -C₄ alkyl substituted with 0-2 R²⁴, C₆ -C₁₀ aryl,C₃ -C₇ cycloalkyl, C₁ -C₆ alkylcarbonyl, C₁ -C₆ alkylaminocarbonyl, C₇-C₁₄ arylalkylcarbonyl, or C₆ -C₁₀ arylcarbonyl substituted with 0-2 R⁹; R¹⁹ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₁ -C₄ alkoxyalkyl, C₁ -C₆alkylcarbonyl, C₁ -C₆ alkylaminocarbonyl, C₇ -C₁₄ arylalkylcarbonyl, orC₆ -C₁₀ arylcarbonyl substituted with 0-2 R⁹ ; R²¹ is C₁ -C₄ alkyl orbenzyl; R²³ is H, F, phenyl substituted with 0-2 R⁹, --C(═O)R⁶,--COOR¹⁷, --C(═O)NHR¹⁶, or a heterocyclic ring system selected frommorpholinyl, piperidinyl, pyrrolidinyl, furyl, thienyl, ortetrahydropyridinyl, said heterocyclic ring system being substitutedwith 0-2 R⁹ ; R²⁴ is H, F, NR¹⁵ R¹⁶, phenyl substituted with 0-2 R⁹, C₁-C₄ alkoxy, C₁ -C₄ alkylcarbonyloxy, C(═O)R⁶, --COOR¹⁷, --C(═O)NR¹⁵ R¹⁶,or a heterocyclic ring system selected from morpholinyl, piperidinyl,pyrrolidinyl, furyl, thienyl, piperidinyl, or tetrahydropyridinyl, saidheterocyclic ring system being substituted with 0-2 R⁹ ; m is 0-2; p is0-1;provided that when J and L are both nitrogen and K is CR⁴, then R⁴cannot be SR¹⁰.
 12. A method of treating pyresis in a mammal comprisingadministering to the mammal in need of such treatment a therapeuticallyeffective amount of a compound of claim 11 selected from the groupconsisting of:2-(4-methylsulfonylphenyl)-3-phenylnaphthalene,3-(4-methylsulfonylphenyl)-2-phenylpyridine, and2-(4-aminosulfonylphenyl)-1-biphenyl.
 13. The compounds whichare:2-(4-methylsulfonylphenyl)-3-phenylnaphthalane,3-(4-methylsulphonylphenyl)-2-phenylpyridine, and2-(4-aminosulfonylphenyl)-1-biphenyl.